Methods of treating gastrointestinal spasms in a subject having Crohn&#39;s Disease or ulcerative colitis

ABSTRACT

Methods of treating gastrointestinal spasms are provided. For example, methods of treating gastrointestinal spasms are provided, such methods not requiring the use of systemic drugs that have shown to (i) provide slow relief, (ii) cause adverse side effects, (iii) limit activities, (iv) worsen existing gastrointestinal conditions, (v) be unrecommended in several gastrointestinal conditions that include gastrointestinal spasms, or (vi) be unrecommended in the absence of diarrhea.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/726,180, filed Dec. 23, 2012, which is hereby incorporated herein byreference in its entirety.

BACKGROUND

1. Field of the Invention

The teachings provided herein relate to methods of treatinggastrointestinal spasms.

2. Description of Related Art

Antispasmodics can be used to prevent spasms of the stomach, intestine,uterus, or urinary bladder. Gastrointestinal spasms, for example, can bevery painful. Abdominal pain and discomfort from cramping, bloating,forceful vomiting, and forceful defecation are often the result ofspasmodic intestinal contractions. The problem is that there is nosatisfactory treatment to relieve the pain and suffering that currentlyexists due to this problem. Spasms can also be treated using“anticholinergics” that counteract the effects of the neurohormoneacetylcholine. The anticholingergics decrease both the movements of thestomach and intestine, and also the secretions of stomach acid anddigestive enzymes. Problems with these drugs include dry mouth and dryeyes because of reduced salivation and tearing.

An example of an anticholinergic that is used to treat cramping isloperamide, an opioid-receptor agonist that slows peristalsis. As such,it is not directed to relieve cramping from spasms, per se. Moreover,loperamide crosses the blood-brain barrier and, although quickly removedfrom the CNS by P-glycoprotein, it can be addictive if taken with a drugthat inhibits P-glycoprotein. Moreover, loperamide has severalcontraindications, such that it's not recommended for use with severalconditions that can include gastrointestinal spasms. For example, it isnot recommended for treatment with conditions containing organisms thatcross the intestinal walls, such as such as E. coli O157:H7 orsalmonella. And, ironically, although it is often administered toalleviate abdominal pain and cramping, its adverse effects can actuallyinclude abdominal pain and bloating, nausea, vomiting and constipation.In fact, loperamide has been labeled as (i) contraindicated in patientswith abdominal pain in the absence of diarrhea; (ii) not recommended inchildren below 24 months of age; and (iii) not recommended as theprimary therapy in patients with (a) acute dysentery, which ischaracterized by blood in stools and high fever; (b) acute ulcerativecolitis; (c) bacterial enterocolitis caused by invasive organismsincluding Salmonella, Shigella, and Campylobacter; or, (d)pseudomembranous colitis associated with the use of broad-spectrumantibiotics. See, for example,http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=41053,Lake Erie Medical DBA Quality Care Products LLC.

A condition of particular interest in the treatment of gastrointestinalspasms is irritable bowel syndrome (IBS), a condition afflicting anestimated 30 million people in the US and up to 700 million peopleworldwide. IBS is diagnosed from clinical symptoms that includeabdominal pain, bloating, constipation, and diarrhea. Treatment optionsare based upon the predominant symptom, with diarrhea-predominant IBSreceiving antidiarrheal agents, such as loperamide (IMMODIUM) andpain-predominant IBS patients receiving antispasmodic agents, such asdicyclomine HCL (BENTRYL) and hyoscyamine sulfate (LEVSIN). Thecondition is generally thought to be the result of spasmodiccontractions of the intestines that interfere with normal peristalsiscausing blockages that lead to bloating and constipation, causehyperperistaltic activity leading to frequent need for defecation, or acombination. Problems with loperamide are discussed above. Dicyclominehas the problem of some people sweat less, allowing the body to overheatwhich can cause heat prostration (fever and heat stroke). As such,anyone taking this drug should try to avoid extreme heat. Moreover,dicyclomine can also cause drowsiness and blurred or double vision, suchthat people who take this drug should not drive, use machines, or doanything else that might be dangerous. Hyoscyamine can also be used but,unfortunately, both dicyclomine and hyoscyamine have general sideeffects and, for example, can worsen gastroesophageal reflux disease.Anticholinergics, generally speaking, are also known to cause difficultyin passing urine, and children and the elderly are at a higher risk ofdeveloping such side effects.

One of skill would appreciate having a method of treating spasms,particularly gastrointestinal spasms, without having to use systemicdrugs that have shown to (i) provide slow relief, (ii) cause adverseside effects, (iii) limit activities, (iv) worsen existinggastrointestinal conditions, (v) be unrecommended in severalgastrointestinal conditions that include gastrointestinal spasms, and(vi) be unrecommended in the absence of diarrhea.

SUMMARY

The teachings provided herein relate to methods of treatinggastrointestinal spasms. The teachings include methods of treatinggastrointestinal spasms without having to use systemic drugs that haveshown to (i) provide slow relief, (ii) cause adverse side effects, (iii)limit activities, (iv) worsen existing gastrointestinal conditions, (v)be unrecommended in several gastrointestinal conditions that includegastrointestinal spasms, or (vi) be unrecommended in the absence ofdiarrhea.

In some embodiments, the teachings are directed to a method of treatinga gastrointestinal spasm in a subject, the method comprisingadministering an effective amount of a composition to a subject having agastrointestinal spasm, the composition having a polyphenol combinedwith a reactive oxygen species. And, in some embodiments, thecomposition can be produced from a process including combining apolyphenol with a reactive oxygen species; selecting a desiredconcentration for the composition; and, diluting the composition to thedesired concentration for the administering. In these embodiments, thepolyphenol can have a molecular weight ranging from about 170 Daltons toabout 4000 Daltons; and, the composition can relieve a gastrointestinalspasm in the subject either (i) when compared to a second subject in acontrol group in which the composition was not administered or (ii) whencompared to a historic baseline of the symptoms present in the subject.The measurement of relief from gastrointestinal spasms can be measuredusing any of a variety of parameters, in some embodiments. For example,the relief of the spasm can be measured using a response selected fromthe group consisting of a reduction in abdominal pain, a reduction inbloating, a reduction in forceful defecation, a reduction in forcefulvomiting, a reduction in defecation urgency, a reduction inconstipation, and/or a reduction in incontinence.

The polyphenol can comprise a single component, a mixture of components,or a whole extract of a plant tissue, in some embodiments. In someembodiments, the polyphenol comprises a tannin. In some embodiments, thepolyphenol comprises a hydrolysable tannin, a condensed tannin, or acombination of a hydrolysable tannin and a condensed tannin. In someembodiments, the polyphenol can comprise a pseudotannin selected, forexample, from the group consisting of gallic acid, which can be found inan extract of a rhubarb plant tissue, for example; flavan-3-ols orcatechins, which can be found in an extract of acacia, catechu, cocoa,or guarana, for example; chlorogenic acid, which can be found in coffee,or mate; or, ipecacuanhic acid, which can be found in carapicheaipecacuanha, for example. As such, it should be appreciated that, insome embodiments, the polyphenol component can comprise a flavanol or acatechin. Moreover, the polyphenol can comprises gallic acid, epigallicacid, or a combination thereof, in some embodiments.

The reactive oxygen species can be any such species known to one ofskill to have the ability to combine with the polyphenol as acomposition for the uses taught herein. In some embodiments, thereactive oxygen species comprises hydrogen peroxide. And, in someembodiments, the hydrogen peroxide can be combined with the tannin at atannin:peroxide weight ratio that ranges from about 1:1000 to about10:1. In some embodiments, the weight ratio of the tannin:peroxideranges from about 1:1 to about 1:50.

And, consistent with the above, one of skill will appreciate that thepolyphenol can be combined with the reactive oxygen species as acomponent of a water or alcohol extract of a plant tissue. In someembodiments, the plant tissue can comprise a tannin or a pseudotannin.

One of skill reading the teachings that follow will appreciate that theconcepts can extend into additional embodiments that go well-beyond aliteral reading of the claims, the inventions recited by the claims, andthe terms recited in the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1H are photographs of the dry forms of (A) gallic acid (a modelpolyphenol building block) bound to hydrogen peroxide; (B) gallic acidalone; (C) tannic acid (a model polyphenol) bound to hydrogen peroxide;(D) tannic acid alone; (E) pomegranate husk extract bound to hydrogenperoxide; (F) pomegranate husk extract alone; (G) green tea extractbound to hydrogen peroxide; and (H) green tea extract alone, accordingto some embodiments.

FIGS. 2A and 2B show that the stability of the hydrogen peroxide in thecombination is consistently, substantially greater in an aqueoussolution than the stability of the hydrogen peroxide alone in theaqueous solution, according to some embodiments.

DETAILED DESCRIPTION

Methods of treating gastrointestinal spasms are provided herein. Themethods include treating gastrointestinal spasms without having to usesystemic drugs. Such systemic drugs have been reported to (i) provideslow relief, (ii) cause adverse side effects, (iii) limit activities,(iv) worsen existing gastrointestinal conditions, (v) be unrecommendedin several gastrointestinal conditions that include gastrointestinalspasms, or (vi) be unrecommended in the absence of diarrhea.

In some embodiments, the method of treating a gastrointestinal spasm ina subject comprises administering an effective amount of a compositionto a subject having a gastrointestinal spasm, the composition having apolyphenol combined with a reactive oxygen species. And, in someembodiments, the composition can be produced from a process includingcombining a polyphenol with a reactive oxygen species; selecting adesired concentration for the composition; and, diluting the compositionto the desired concentration for the administering. In theseembodiments, the polyphenol can have a molecular weight ranging fromabout 170 Daltons to about 4000 Daltons; and, the composition canrelieve a gastrointestinal spasm in the subject either (i) when comparedto a second subject in a control group in which the composition was notadministered or (ii) when compared to a historic baseline of thesymptoms present in the subject.

To provide a desired therapeutic relief, the compositions can bedirected to act on tissues at a particular target site, which can begastrointestinal tissue, in some embodiments. The term “target site” canbe used to refer to a select location at which the composition acts toprovide a therapeutic effect, or treatment as described herein. In someembodiments, the target site can be a tissue of any organ in whichcontrol of a spasm is desirable. Moreover, the target can include anysite of action in which the phenolic compound can be site-activated byan oxidoreductase enzyme that is available at the site. Theoxidoreductase enzyme can be produced endogenously by a tissue at atarget site, produced endogenously by a microbe, introduced exogenouslyto the target site, include more than one enzyme, co-enzyme, catalyst,or cofactor, or a combination thereof. The measurement of relief fromgastrointestinal spasms, for example, can be measured using any of avariety of parameters. For example, the relief of the spasm can bemeasured using a response selected from the group consisting of areduction in abdominal pain, a reduction in bloating, a reduction inforceful defecation, a reduction in forceful vomiting, a reduction indefecation urgency, a reduction in constipation, and/or a reduction inincontinence.

Without intending to be bound by any theory or mechanism of action, thecompositions taught herein can include phenolics, for example,polyphenols. The phenolic compounds taught herein are selected tocombine with a reactive oxygen species to form a composition that isdeliverable as a stable, or substantially stable, system. In someembodiments, the compositions can include a polyphenol componentcombined with hydrogen peroxide, a combination of components having anassociation that offers a stability and activity, both of which areoffered by neither component alone. Such a composition can be deliveredto a target site, for example, in a polar solution such as water or analcohol. In some embodiments, at least a substantial amount of thehydrogen peroxide can remain bound, or otherwise associated with, andthus stable or substantially stable, with the phenolic compound.Moreover, in some embodiments, the composition contains no, orsubstantially no, unbound hydrogen peroxide. The teachings also includea pharmaceutical formulation comprising the compositions taught hereinand a pharmaceutically acceptable excipient.

The terms “composition,” “compound,” “binding system,” “binding pair,”and “system” can be used interchangeably in some embodiments and, itshould be appreciated that a “formulation” can comprise a composition,compound, binding system, binding pair, or system presented herein.Likewise, in some embodiments, the compositions taught herein can alsobe referred to as an “agent,” a “bioactive agent,” or a “supplement”whether alone, in a pharmaceutically acceptable composition orformulation, and whether in a liquid or dry form. Moreover, the term“bioactivity” can refer to a treatment that occurs through the use ofthe compositions provided herein. One of skill will appreciate that theterm “bind,” “binding,” “bound,” “attached,” “connected,” “chemicallyconnected,” “chemically attached,” “combined,” or “associated” can beused interchangeably, in some embodiments. Such terms, for example, canbe used to refer to any association between the polyphenol and reactiveoxygen species that has resulted in an increased stability and/orsustained activity of the composition or components in the compositions.For example, the terms can be used to describe a chemical bondingmechanism known to one of skill, such as covalent, ionic, dipole-dipoleinteractions, London dispersion forces, and hydrogen bonding, forexample. In some embodiments, the compositions can comprise a phenoliccompound sharing hydrogen bonds with a reactive oxygen species, forexample, such as hydrogen peroxide. In some embodiments, the phenoliccompound can comprise a polyphenol that covalently binds to an aminoacid or polyol.

One of skill will appreciate that the compositions should remain stable,or at least substantially stable, until useful or activated, and thiscan relate to a measure of time. Such a measure of time can include ashelf life, or a time between creation of the composition andadministration of the composition, or some combination thereof. In someembodiments, the composition is stable, or substantially stable, whenusable as intended within a reasonable amount of time. In someembodiments, the composition should be usable within a reasonable timefrom the making of the composition to the administration of thecomposition and, in some embodiments, the composition should have areasonable commercial shelf life. The composition can be considered as“stable” if it loses less than 10% of it's original oxidation potential,and this can be measured by comparing it's oxidation potential aftermaking the composition to the time of administration, and this caninclude a reasonable shelf life, in some embodiments. In someembodiments, the composition can be considered as stable if it losesless than 5%, 3%, 2%, or 1% of it's original oxidation potential whencomparing it's oxidation potential after making the composition to thetime of administration, and this can include a reasonable shelf life, insome embodiments. The composition can be considered as “substantiallystable” if it loses greater than about 10% of it's original oxidationpotential, as long as the composition can perform it's intended use to areasonable degree of efficacy. The loss can be measured, as above, bymeasured by comparing it's oxidation potential after making thecomposition to the time of administration, and this can include areasonable shelf life, in some embodiments. In some embodiments, thecomposition can be considered as substantially stable if a reactiveoxygen species loses greater than about 12%, about 15%, about 25%, about35%, about 45%, about 50%, about 60%, or even about 70% of it's originaloxidation potential. The loss may be measured by measured by comparingit's oxidation potential after making the composition to the time ofadministration, and this can include a reasonable shelf life, in someembodiments. The time to compare the oxidation potential for a measureof stability can range from about 30 minutes to about one hour, fromabout one hour to about 12 hours, from about 12 hours to about 1 day,from about one day to about one week, from about 1 week to about 1month, from about 1 month to about 3 months, from about 1 month to ayear, from 3 months to a year, from 3 months to 2 years, from 3 monthsto 3 years, greater than 3 months, greater than 6 months, greater thanone year, or any time or range of times therein, stated in increments ofone hour.

One of skill will appreciate that the phenolic compound used in thecompositions can be any phenolic compound that functions consistent withthe teachings provided herein, and there are at least several thousandsuch phenolic compounds known to those of skill that can be expected tofunction as desired. As such, the teachings provided herein can onlyinclude examples of the general concepts rather than a comprehensivelisting of all possibilities and permutations of the systems that areenabled by the teachings.

The phenolic component can be a polyphenol, and the polyphenol cancomprise a single component, a mixture of components, or a whole extractof a plant tissue, in some embodiments. In some embodiments, thepolyphenol comprises a tannin. In some embodiments, the polyphenolcomprises a hydrolysable tannin, a condensed tannin, or a combination ofa hydrolysable tannin and a condensed tannin. In some embodiments, thepolyphenol can comprise a pseudotannin selected, for example, from thegroup consisting of gallic acid, which can be found in an extract of arhubarb plant tissue, for example; flavan-3-ols or catechins, which canbe found in an extract of acacia, catechu, cocoa, or guarana, forexample; chlorogenic acid, which can be found in coffee, or mate; or,ipecacuanhic acid, which can be found in carapichea ipecacuanha, forexample. As such, it should be appreciated that, in some embodiments,the polyphenol component can comprise a flavanol or a catechin.Moreover, the polyphenol can comprises gallic acid, epigallic acid, or acombination thereof, in some embodiments.

In some embodiments, the phenolic compound has at least one aryl group,or arene moiety, and at least two polar aromatic groups, such asaromatic hydroxyl groups. In some embodiments, the polar aromatic groupscan be, for example, hydroxyl, amine, amide, acyl, carboxy, or carbonyl.In some embodiments, the phenolic compound has at least two aryl groups,and at least two hydroxyl groups. In some embodiments, the phenoliccompounds can be naturally occurring, such as from a plant or othernatural product. And, in some embodiments, the phenolic compounds can besynthetically or semi-synthetically produced. The compounds can besimple monomers, oligomers, or polymers. The polymers can be in theclass of polyphenols or polymeric phenols, where one of skill willunderstand that the general difference is typically that polyphenolsgenerally do not have a repeating unit, whereas polymeric phenols do.There are exceptions, however, such that groups of polyphenols andpolymeric phenols can overlap. In most embodiments, the phenoliccompound used in the binding system can be any phenolic compound taughtherein, or any prodrugs, codrugs, metabolites, analogs, homologues,congeners, derivatives, salts, solvates, and combinations thereof.

In some embodiments, the phenolic compounds bind to hydrogen peroxide toform a binding pair and, in some embodiments, the binding pair remainsstable, or substantial stable in water. In some embodiments, the bindingpair remains stable, or substantial stable in an alcohol. And, in someembodiments, the binding pair remains stable, or substantial stable, ina polar solvent such as, for example, a saline solution, an aqueousemulsion, a hydrogel, and the like.

In some embodiments, the phenolic compounds are polyphenols havingmolecular weights ranging from about 170 to about 4000 Daltons, havingfrom about 12 to about 16 phenolic hydroxyl groups, and having fromabout five to about seven aromatic rings, for every about 1000 Daltonsin molecular weight. In some embodiments, the phenolic compoundsfunction to precipitate alkaloids and proteins. In some embodiments, thephenolic compounds can bind to cellular receptors, amino acids,peptides, oligopeptides, polyols, saccharides, or combinations thereof.In some embodiments, the phenolic compounds have at least from about 1to about 20 polyhydroxylated phenolic units and have at least moderatewater solubility.

The term “solubility” can refer to a concentration of a solute in asolvent, for example, the phenolic compound in water. The concentrationcan be expressed by mass, for example, mg of the phenolic compound perkg of water at ambient temperature and pressure. This ratio of mg/kg canbe used interchangeably with ppm, and ng/kg can be used interchangeablywith ppb. In some embodiments, the solubility of the phenolic compoundcan be higher than about 500,000 ppm or less than about 1 ppm. In someembodiments, the solubility of the phenolic compound range from about 10ppb to about 500,000 ppm, from about 100 ppb to about 250,000 ppm, fromabout 1 ppm to about 100,000 ppm, from about 10 ppm to about 50,000 ppm,from about 50 ppm to about 25,000 ppm, from about 100 ppm to about10,000 ppm, from about 100 ppm to about 100,000 ppm, from about 200 ppmto about 100,000 ppm, from about 250 ppm to about 50,000 ppm, from about500 ppm to about 25,000 ppm from about 250 ppm to about 10,000 ppm, orany range therein. In some embodiments, the solubility can range fromabout 1 g/L to about 10,000 g/L, from about 5 g/L to about 5000 g/L,from about 10 g/L to about 3000 g/L, from about 20 g/L to about 2000g/L, from about 50 g/L to about 1000, g/L, from about 100 g/L to about500 g/L, or any range therein. For purposes of the teachings providedherein, a compound can be considered to have a low solubility if thesolubility is less than about 50 g/L, a moderate solubility if thesolubility ranges from about 50 g/L to about 1000 g/L, and a highsolubility if the solubility is above about 1000 g/L. In someembodiments, the phenolic compound can have a low solubility. In someembodiments, the phenolic compound can have a moderate solubility. And,in some embodiments, the phenolic compound can have a high solubility.

One of skill will appreciate that the phenolic compounds can still beuseful at low solubilities in cases where the solubility is too low toform a true solution. In some embodiments the phenolic compounds can beground into particles to form a colloidal mixture or suspension thatwill function consistent with the teachings provided herein. As such,liquid formulations include colloids and suspensions in someembodiments. The formulations can be a dispersed phase mixture in theform of colloidal aerosols, colloidal emulsions, colloidal foams,colloidal dispersions, or hydrosols. In some embodiments, the liquidformulation can include particles having sizes ranging, for example,from about 5 nm to about 200 nm, from about 5 nm to about 500 nm, fromabout 5 nm to about 750 nm, from about 50 nm to about 1 um. In someembodiments, the liquid formulations can be suspensions, in which theparticle size range from about 1 um to about 10 um, from about 1 um toabout 7 um, from about 1 um to about 5 um, or any range therein. In someembodiments, the liquid formulation can include particles having sizesranging from about 1 nm to about 10 um.

The functionality of a phenolic compound in the teachings herein can,for at least the reason of solubility, depend on molecular weight, aloneor in addition to other factors discussed herein such as, for example,extent of hydroxylation, presence and location of ketone or quininegroups, and the presence of other functional groups. In someembodiments, the molecular weights of the phenolic compounds can rangefrom about 110 Daltons to about 40,000 Daltons. In some embodiments, themolecular weights of the phenolic compounds can range from about 200Daltons to about 20,000 Daltons, from about 300 Daltons to about 30,000Daltons, from about 400 Daltons to about 40,000 Daltons, from about 500Daltons to about 10,000 Daltons, from about 1000 Daltons to about 5,000Daltons, from about 170 Daltons to about 4000 Daltons, from about 350Daltons to about 4,000 Daltons, from about 300 Daltons to about 3,000Daltons, from about 110 Daltons to about 2,000 Daltons, from about 200to about 5000 Daltons, or any range or molecular weight therein inincrements of 10 Daltons.

In some embodiments, the ratio of aromatic rings to molecular weight ofthe phenolic compounds can range from about five to about seven aromaticrings for every about 1000 Daltons. In some embodiments, the ratio ofaromatic rings to molecular weight of the phenolic compounds can rangefrom about 2 to about 10 aromatic rings for every about 1000 Daltons,from about 3 to about 9 aromatic rings for every about 1000 Daltons,from about 4 to about 8 aromatic rings for every about 1000 Daltons,from about 5 to about 7 aromatic rings for every about 1000 Daltons,from about 1 to about 5 for every about 500 Daltons, from about 1 toabout 4 for every about 500 Daltons, from about 1 to about 3 for everyabout 500 Daltons, from about 2 to about 4 for every about 500 Daltons,or any amount or range therein in increments of 1 ring.

One of skill will appreciate that, in some embodiments the phenoliccompounds can have, or be synthesized or otherwise designed to containfunctional groups that are capable of releasably bonding to a reactiveoxygen species, in a stable or substantially stable form, until eitherconsumed or released upon bioactivation at a target site. In someembodiments, a releasable bond can include any bond other than acovalent bond. In some embodiments, a releasable bond is a hydrogenbond. As such, the phenolic compounds should be capable of forming, forexample, a hydrogen bond with a reactive oxygen species upon suchbioactivation. In some embodiments, the phenolic compound shareshydrogen bonding with hydrogen peroxide and is released through abioactivation that occurs when the binding pair comes into contact withan oxidoreductase enzyme or other reducing agent. In some embodiments,the phenolic compound can have functional groups that comprise acyl,amido, amino, carbonyl, carboxyl, hydroxyl, or peroxyl functionality. Insome embodiments, the hydrogen bond between the reactive oxygen speciesand the phenolic compound can include any hydrogen donor and anyhydrogen acceptor having an available lone pair of electrons. In someembodiments, the hydrogen acceptor can include, for example a N, O, or Fatom, or a combination thereof. In some embodiments, the phenoliccompound can have such a functionality, can be derivatized to have sucha functionality, can be linked to another compound having such afunctionality, can be placed in a carrier having such a functionality,or some combination thereof.

In some embodiments, phenolic compounds can include simple phenols, suchas those containing 6 carbons, a C6 structure, and 1 phenolic cycle,such as the benzene alcohols, examples of which include phenol, benzenediols and it's isomers such as catechol, and the benzenetriols. In someembodiments, phenolic compounds can include phenolic acids andaldehydes, such as those containing 7 carbons, a C6-C1 structure, and 1phenolic cycle, examples of which include gallic acid and salicylicacids. In some embodiments, phenolic compounds can include, for example,tyrosine derivatives, and phenylacetic acids, such as those containing 8carbons, a C6-C2 structure, and 1 phenolic cycle, examples of whichinclude 3-acetyl-6-methoxybenzaldehyde, tyrosol, andp-hydroxyphenylacetic acid. In some embodiments, phenolic compounds caninclude hydroxycinnamic acids, phenylpropenes, chromones, such as thosecontaining 9 carbons, a C6-C3 structure, and 1 phenolic cycle, examplesof which include caffeic acid, ferulic acids, myristicin, eugenol,umbelliferone, aesculetin, bergenon, and eugenin. In some embodiments,phenolic compounds can include naphthoquinones, such as those containing10 carbons, a C6-C4 structure, and 1 phenolic cycle, examples of whichinclude juglone and plumbagin. In some embodiments, phenolic compoundscan include xanthonoids, such as those containing 13 carbons, a C6-C1-C6structure, and 2 phenolic cycles, examples of which include mangiferin.In some embodiments, phenolic compounds can include stilbenoids, andanthraquinones, such as those containing 14 carbons, a C6-C2-C6structure, and 2 phenolic cycles, examples of which include resveratroland emodin. In some embodiments, phenolic compounds can includechalconoids, flavonoids, isoflavonoids, and neoflavonoids, such as thosecontaining 15 carbons, a C6-C3-C6 structure, and 2 phenolic cycles,examples of which include quercetin, myricetin, luteolin, cyanidin, andgenistein. In some embodiments, phenolic compounds can include lignansand neolignans, such as those containing 18 carbons, a C6-C3-C6structure, and 2 phenolic cycles, examples of which include pinoresinoland eusiderin. In some embodiments, phenolic compounds can includebiflavonoids, such as those containing 30 carbons, a (C6-C3-C6)₂structure, and 4 phenolic cycles, examples of which includeamentoflavone. In some embodiments, phenolic compounds can includepolyphenols, polyphenolic proteins, lignins, and catechol melanins, suchas those containing >30 carbons. In these embodiments, the phenoliccompounds can have, for example, a (C6-C3)_(n) structure, a (C6)_(n)structure, a (C6-C3-C6)_(n) structure, or some combination thereof, aswell as greater than about 12 phenolic cycles. Examples of suchembodiments can include, for example, the flavolans, in the class ofcondensed tannins.

In some embodiments, the phenolic compounds are natural phenols that canbe enzymatically polymerized. Derivatives of natural phenols can also beused in some embodiments. These embodiments can include phenoliccompounds having less than 12 phenolic groups, such that they can rangefrom monophenols to oligophenols. In some embodiments, the naturalphenols are found in plants, have an antioxidant activity, or acombination thereof. Examples of the natural phenols include, forexample, catechol- and resorcinol-types (benzenediols) with two phenolichydroxy groups, and pyrogallol- and phloroglucinol-types (benzenetriols)with three hydroxy groups. Natural phenols may have heteroatomsubstituents other than hydroxyl groups, ether and ester linkages,carboxylic acid derivatives, or some combination thereof. In someembodiments, the natural phenols include natural phenol drugs and theirderivatives. Examples of such drugs include, but are not limited to,anthraquinone drugs, flavone drugs, and flavonol drugs. Examples ofanthraquinone drugs include, but are not limited to, aloe emodin,aquayamycin, and diacerein. Examples of flavone drugs include, but arenot limited to, ansoxetine and hidrosmin. Examples of flavonol drugsinclude, but are not limited to, monoxerutin and troxerutin.

In some embodiments, the phenolic compound is a tannin, a polyphenolicphenylpropanoid, or a combination thereof. In some embodiments, thetannin is a hydrolysable tannin, a condensed tannin, or a combinationthereof. Hydrolysable tannins can be found, for example, in chinesegall, which is almost pure in that it has no or substantially nocondensed tannins. Condensed tannins can be found, for example, in greentea leaf, which is also almost pure in that it has no or substantiallyno hydrolysable tannins.

Examples of hydrolysable tannin can include gallotannic acids,quercitannic acids, ellagitannins, gallotannin, pentagalloyl glucose,galloylquinic acid, galloyl-shikimic acid, and punicalagin. In someembodiments, the hydrolysable tannin is a gallotannin or ellagitannin,and isomers thereof, such as isomers that can precipitate protein.Examples of gallotannins include the gallic acid esters of glucose intannic acid (C₇₆H₅₂O₄₆) and pentagalloyl glucose (PGG), and isomersthereof, such as the isomers of PGG that function to precipitateproteins. Examples of an ellagitannin include castalin and punicalagin.In some embodiments, the tannin is a gallic acid ester having amolecular weight ranging from about 500 Daltons to about 3000 Daltons.In some embodiments, the tannin is a proanthocyanidin having a molecularweight of up to about 20,000 Daltons. In some embodiments, thehydrolysable tannins are derivatives of gallic acid and characterized bya glucose, quinic acid or shikimic acid core with its hydroxyl groupspartially or totally esterified with gallic acid or ellagic acid groups.The compounds can have 3 to 12 galloyl residues but may be furtheroxidatively crosslinked and complex. Hydrolysable tannins can be readilysynthesized, for example, to obtain a phenolic compound with a highnumber of polar functional groups that form multiple, stable hydrogenbonds between the tannin and hydrogen peroxide in the binding system.

It should be appreciated that, while hydrolysable tannins and mostcondensed tannins are water soluble, some very large condensed tanninsare insoluble. In some embodiments, the phenolic compound can comprise ahydrolysable tannin such as, for example, burkinabin C, castalagin,castalin, casuarictin, chebulagic acid, chebulinic acid, corilagin,digallic acid, ellagitannin, gallagic acid, gallotannin, glucogallin,grandinin, hexahydroxydiphenic acid, pentagalloyl glucose, punicalaginalpha, punicalagins, raspberry ellagitannin, roburin A, stenophyllaninA, stenophyllanin A, tannate, tannic acid, tellimagrandin II, terflavinB, or 3,4,5-tri-O-galloylquinic acid.

In some embodiments, the phenolic compound can be a flavonoid whichincludes several thousand natural phenol compounds. Examples of theflavonoids include the flavonols, flavones, flavan-3ol (catechins),flavanones, anthocyanidins, isoflavonoids, and hybrids of anycombination of these compounds. In some embodiments, the phenoliccompounds are the hydrolysable tannins such as, for example, gallicacid. In some embodiments, the phenolic compounds are the lignins suchas, for example, cinnamic acid. In some embodiments, the phenolic unitscan be dimerized or further polymerized to form any of a variety ofhybrids. For example, ellagic acid is a dimer of gallic acid and formsthe class of ellagitannins, or a catechin and a gallocatechin cancombine to form theaflavin or the large class of thearubigins found intea. In another example, a flavonoid and a lignan can combine to form ahybrid, such a flavonolignans.

In some embodiments, the phenolic compound can be a flavan-3ol. Examplesinclude the catechins and the catechin gallates, where the catechingallates are gallic acid esters of the catechins. In some embodiments,the phenolic compound is a catechin or epicatechin compound (the cis- ortrans-isomers). In some embodiments, the phenolic compound is(−)-epicatechin or (+)-catechin. In some embodiments, the phenoliccompound is epigallocatechin (EGC) or gallocatechin (EC). In someembodiments, the phenolic compound is a catechin gallate, such asepigallocatechin gallate (EGCG)

In some embodiments, the phenolic compound can be selected from thegroup of flavones consisting of apigenin, luteolin, tangeritin,flavonols, isorhamnetin, kaempferol, myricetin (e.g., extractable fromwalnuts), proanthocyanidins or condensed tannins, and quercetin andrelated phenolic compounds, such as rutin.

In some embodiments, the phenolic compound can be selected from thegroup of flavanones consisting of eriodictyol, hesperetin (metabolizesto hesperidin), and naringenin (metabolized from naringin).

In some embodiments, the phenolic compound can be selected from thegroup of flavanols consisting of catechin, gallocatechin and theircorresponding gallate esters, epicatechin, epigallocatechin and theircorresponding gallate esters, theaflavin and its gallate esters,thearubigins, isoflavone phytoestrogens (found primarily in soy,peanuts, and other members of the Fabaceae family), daidzein, genistein,glycitein, stilbenoids, resveratrol (found in the skins of dark-coloredgrapes, and concentrated in red wine), pterostilbene (methoxylatedanalogue of resveratrol, abundant in Vaccinium berries), anthocyanins,cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin.And, In some embodiments, the phenolic compound can be ubiquinol anelectron-rich (reduced) form of coenzyme Q10.

In some embodiments, the phenolic compound can be selected from thegroup of carotenoid terpenoid consisting of alpha-carotene, astaxanthin(found naturally in red algae and animals higher in the marine foodchain, a red pigment familiarly recognized in crustacean shells andsalmon flesh/roe), beta-carotene (found in high concentrations inbutternut squash, carrots, orange bell peppers, pumpkins, and sweetpotatoes), canthaxanthin, lutein (found in high concentration inspinach, kiwifruit and red peppers), lycopene (found in highconcentration in ripe red tomatoes and watermelons) and zeaxanthin (themain pigment found in yellow corn, also abundant in kiwifruit).

In some embodiments, the phenolic compound can be selected from thegroup of phenolic acids and their esters consisting of chicoric acid(another caffeic acid derivative, is found only in the medicinal herbechinacea purpurea), chlorogenic acid (found in high concentration incoffee (more concentrated in robusta than arabica beans, blueberries andtomatoes, and produced from esterification of caffeic acid), cinnamicacid and its derivatives, such as ferulic acid (found in seeds of plantssuch as in brown rice, whole wheat and oats, as well as in coffee,apple, artichoke, peanut, orange and pineapple), ellagic acid (found inhigh concentration in raspberry and strawberry, and in ester form in redwine tannins), ellagitannins (hydrolysable tannin polymer formed whenellagic acid, a polyphenol monomer, esterifies and binds with thehydroxyl group of a polyol carbohydrate such as glucose), gallic acid(found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and manyother plants), gallotannins (hydrolysable tannin polymer formed whengallic acid, a polyphenol monomer, esterifies and binds with thehydroxyl group of a polyol carbohydrate such as glucose), rosmarinicacid (found in high concentration in rosemary, oregano, lemon balm,sage, and marjoram), and salicylic acid (found in most vegetables,fruits, and herbs; but most abundantly in the bark of willow trees, fromwhere it was extracted for use in the early manufacture of aspirin).

In some embodiments, the phenolic compound can be selected from thegroup of nonflavonoid phenolics consisting of curcumin (has lowbioavailability, because, much of it is excreted throughglucuronidation, but bioavailability can be substantially enhanced bysolubilization in a lipid (oil or lecithin), heat, addition of piperine,or through nanoparticularization, flavonolignans, for example, silymarinwhich is a mixture of flavonolignans extracted from milk thistle),eugenol and xanthones (mangosteen, for example, is purported to containa large variety of xanthones, some of which, like mangostin are believedto be present only in the inedible shell).

In some embodiments, the phenolic compound can have a low molecularweight (less than about 400 Daltons), selected from the group consistingof caffeic acid, gentisic acid, protocatechuic acid, phenylacetic acid,gallic acid, phloroglucinol carboxylic acid, and derivatives thereof.Such compounds can form a sufficiently soluble binding pair, and theirrelatively high hydroxyl group to molecular weight ratio createsfavorable conditions for obtaining the intermolecular hydrogen bondsdesired for the binding systems.

In some embodiments, the phenolic compounds can be from a naturalextract, such as an extract of a plant or other natural product. See,for example, U.S. Published Patent Application Nos. 20100158885 and20110070198, each of which is hereby incorporated by reference herein inits entirety. Those skilled in the art of such extracts will understandthat extracts of plant materials are not typically pure in one type ofphenolic compound. Plant tannin extracts, for example, typicallycomprise heterogenous mixtures and derivatives of the above classes.

One of skill will appreciate, given the teachings provided herein, thatthe polyphenol can be combined with the reactive oxygen species as acomponent of a water or alcohol extract of a plant tissue. In someembodiments, the plant tissue can comprise a tannin or a pseudotannin.In some embodiments, the phenolic compound is extracted from a whole orpartial plant tissue selected from the group consisting of seeds andfruits; ovaries; juice; pulp; galls; husks; bark; stems; leaves;flowers; sheaths; hulls; sprouts; bulbs; hips; tubers; roots of grains;grasses; legumes; trees; vegetables; medicinal herbs; tea leaves;algaes; marine plants; and, forages. One of skill will appreciate thatthe type and content of phenolic compound obtained can be expected tovary with the species, season, geographical location, cultivation, andstorage. Examples of plant tissues include, but are not limited to,plant tissues from the species of Aloe, Pachycereus, and Opuntia. Otherexamples can include, but are not limited to, Agavaceae, Cactaceae,Poaceae, Theaceae, Leguminosae, and Lythraceae. In some embodiments, theplant tissues can be selected from the group consisting of pomegranatehusk, aloe vera leaves, and green tea leaves. Other examples of planttissues can include, but are not limited to Aloe (Aloe vera), Angelica(Angelica archangelica), Barberry (Berberis vulgaris) Root Bark,Bilberry (Vaccinium myrtillus), Calendula (Calendula officinalis), Crampbark (Viburnum opulus), Eleutherococcus root (Eleutherococcussenticosus), Kidney wood (Eysenhardtia orththocarpa), Mimosa tenuiflora,Papaya (Carica papaya) leaves, Pau D′ Arco (Tabebuia avellanedae),Sassafras albidum root bark, Saw Palmatto (Serenoa repens), St John'swort (Hypericum perforatum), Valerian (Valeriana officinalis), Apple(Malus domestica), Grape (Vitis vinifera), Echinacea purpurea, Grapeseed extract, and Blueberry (Vaccinium corymbosum). In some embodiments,the plant tissues are selected from the group consisting of barley germ,green tea leaves, aloe vera leaves, mung beans, carrot, cereal grains,seeds, buds, and sprouts.

Likewise, one of skill will appreciate that there are numerous reactiveoxygen species that can be used in the systems taught herein, as long asthe reactive oxygen species function consistent with such teachings.Hydrogen peroxide, and precursors of hydrogen peroxide, are merelyexamples. In some embodiments, the phenolic compounds in thecompositions (i) have phenolic hydroxyl groups that are oxidizable inthe presence of a reactive oxygen species and an oxidoreductase enzyme,and (ii) are soluble in a polar liquid, such as water or an alcohol, forexample, or at least moderately soluble. The phenolic compounds shouldalso be (iii) non-toxic to a subject upon administration. And, in someembodiments, the phenolic compounds should also (iv) crosslink orpolymerize with itself or other phenolic compounds in the compositionstaught herein.

The reactive oxygen species can be any such species known to one ofskill to have the ability to combine with the polyphenol as acomposition for the uses taught herein. For example, the reactive oxygenspecies can include, but is not limited to, the reactive oxygen speciesincludes a component selected from the group consisting of hydrogenperoxide, superoxide anion, singlet oxygen, and a hydroxyl radical. Insome embodiments, the reactive oxygen species comprises hydrogenperoxide. And, in some embodiments, the hydrogen peroxide can becombined with the tannin at a tannin:peroxide weight ratio that rangesfrom about 1:1000 to about 10:1. In some embodiments, the weight ratioof the tannin:peroxide ranges from about 1:1 to about 1:50. In someembodiments, the exogeneous reactive oxygen species can be generated, ashydrogen peroxide for example, from a solid hydrogen peroxide generatingmaterial selected from the group consisting of sodium percarbonate,potassium percarbonate, a carbamide peroxide, and urea peroxide.

In some embodiments, the reactive oxygen species is hydrogen peroxide ormaterials that release or generate hydrogen peroxide including, but notlimited to, hydration of adducts of hydrogen peroxide such as carbamideperoxide, magnesium peroxide, and sodium percarbonate; aminoperhydrates; superoxide dismutase decomposition of ozone, superoxides orsuperoxide salts; glucose oxidase and glucose, aqueous dilution ofhoney; H₂O₂ production by lactobacillus; catalytic quinonehydrogenation; superoxides; and, superoxide dismutase. In someembodiments, the reactive oxygen species can include peroxide ion,organic peroxides, organic hydroperoxides, peracid superoxides,dioxygenyls, ozones, and ozonides. hydrogen peroxide or materials thatgenerate hydrogen peroxide can be obtained or derived synthetically orfrom plant tissues or combinations of plant tissues.

Enzymes can activate the compositions for the methods taught herein, andthe systems for the methods of treatment can be designed accordingly.And, generally speaking, one of skill will appreciate that there are awide variety of enzymes are possible and can be target site dependent.Generally, the enzymes fall into the classes of oxidoreductases. Assuch, there are several enzymes and isozymes that will be present at atarget site and capable of bioactivating the binding systems. In someembodiments, the oxidoreductases can be categorized into about 22classes, and the selectivity of the bioactivation of the binding systemat a target site depends, at least in part, on the selectivity of theoxidoreductase at the target site. In some embodiments, theoxidoreductase can include those oxidoreductases that act on the CH—OHgroup of donors (alcohol oxidoreductases, for example; EC Number class1.1). In some embodiments, the oxidoreductase can include thoseoxidoreductases that act on diphenols and related substances as donors(catechol oxidase, for example, EC Number class 1.10). In someembodiments, the oxidoreductase can include those oxidoreductases thatact on peroxide as an acceptor (peroxidases, such as horseradishperoxidase and catalase; EC Number class 1.11). In some embodiments, theoxidoreductase can include those oxidoreductases that act on phenols asan acceptor (tyrosinases, for example; EC Number class 1.14). Examplesof other useful enzymes for the teachings provided herein include, butare not limited to, glutathione peroxidase 1 and 4 (in many mammaliantissues), glutathione peroxidase 2 (in intestinal and extracellularmammalian tissues), glutathione peroxidase 3 (in plasma mammaliantissues), lactoperoxidase, myeloperoxidase (in salivary & mucosalmammalian tissues), myeloperoxidase (in neutrophil mammalian tissues),cytochrome peroxidase (in yeasts such as Candida albicans) andhorseradish peroxidase (common to show in vitro activity). One of skillwill appreciate that oxidoreductases are selective and, in someembodiments, the oxidoreductase can include an alternate enzyme that areselective for a binding system having a phenolic compound that acts as asubstrate for the alternative enzyme.

In some embodiments, the oxidoreductases include mono-oxygenases suchas, for example, phenylalaning monooxygenase, tyrosine monooxygenase,and tryptophan monooxygenase. In some embodiments, the oxidoreductasesinclude dioxygenases such as, for example, tryptophan dioxygenase,homogentisate dioxygenase, trimethyl lysine dioxygenase, and nitricoxide synthase. In some embodiments, the oxidoreductases includeperoxidases such as, for example, catalase, myeloperoxidase,thyroperoxidase,. In some embodiments, the oxidoreductases act in thepresence of a co-factor or co-enzyme, such as nicotinamide adeninedinucleotide phosphate (NADP) or nicotinamide adenine dinucleotide(NAD).

Methods of Making the Compositions

The design of the binding systems include (i) selecting the phenoliccompound, (ii) selecting the reactive oxygen species, (iii) selectingthe ratio of phenolic compound to reactive oxygen species, and (iv)selecting a carrier. In some embodiments, the phenolic compound can bederivatized or attached to another chemical moiety via a linker, oranother known method such as, for example, esterification to facilitateor improve an association between the phenolic compound and the reactiveoxygen species, as well as to potentially modify, solubility, tissueabsorption, or toxicity.

One of skill will appreciate that, at least from the teachings providedherein, there are a vast number of components that can be selected, theselection of which is, at least in part, dependent on type of enzyme,co-enzymes, cofactors or catalysts present at the target site for thebioactivation of the system. The design of the system can include forexample, (i) identifying the target site; (ii) identifying an enzyme,co-enzymes, cofactors, or catalysts present at the target site but notpresent at tissue surrounding the target site; (iii) selecting a bindingpair for activation at the target site by the enzyme, co-enzymes,cofactors, or catalysts; and, (iv) selecting a carrier in which thebinding pair is stable or substantially stable. Identifying the targetsite can include, for example, select a target tissue for treatment,such as a spastic tissue at which the enzyme, co-enzymes, cofactors orcatalysts present. In some embodiments, the target site is a GI tissue,at which peroxidase or oxidase may be present. Identifying an enzyme,co-enzymes, cofactors, or catalysts present at the target site but notpresent at tissue surrounding the target site can include, for example,identifying the tissue type, as well as the presence of a microbe.Anaerobic pathogens such as Pseudomonas and Vibrio, for example, canexpress a peroxide or an oxidase, making these enzymes available at thetarget site.

After the system and environment of use are known, one of skill canselect a carrier in which the composition is stable or substantiallystable. In one example, the binding system can comprise a mixture ofphenolic compounds in a desired ratio with hydrogen peroxide. Forexample, the phenolic compounds can include a mixture of a pomegranateextract and a green tea extract, and the ratio of phenolic compound tohydrogen peroxide can range from about 1:2 to about 1:20 on a wt/wtbasis, which can include molar weight bases. In some embodiments, thehydrogen peroxide can be added to the phenolic compound using aconcentration of about 0.01% to about 10% hydrogen peroxide solution,and any free hydrogen peroxide can remain or be removed using theteachings provided herein. One of skill can easily select the dose for aparticular use, which will vary according to factors that include theenvironmental conditions at the site of use. In another example, thecompositions can comprise a mixture of phenolic compounds in a desiredratio with hydrogen peroxide. For example, the phenolic compounds caninclude a mixture of a pomegranate extract and a green tea extract, andthe ratio of phenolic compound to hydrogen peroxide can range from about3:1 to about 1:3 on a wt/wt basis (e.g., molar weight). The hydrogenperoxide can be added to the phenolic compound using a concentration ofabout 0.01% to about 10% hydrogen peroxide. In some embodiments, a 35%hydrogen peroxide stock solution can be used as a source of hydrogenperoxide, which can be obtained from a commercially available stocksolution, for example. In some embodiments, up to 60% hydrogen peroxidestock solution can be used as a source of hydrogen peroxide. In fact,higher concentrations are available, and could be used in someembodiments if handled properly. One of skill will be able to readilyselect, obtain and/or produce desired concentrations of hydrogenperoxide. Again, one of skill can easily select the dose for aparticular use, which will vary according to factors that includeenvironmental conditions at the site of use. In some embodiments, thisformulation has worked well for uses in animals that are non-humans.

The compositions can include, for example, a weight (molar or mass)ratio of phenolic compound to reactive oxygen species that ranges fromabout 1:1000 to about 1000:1. In some embodiments, the ratio of phenoliccompound to reactive oxygen species can range from about 1:1000 to about500:1, from about 1:500 to about 500:1, from about 1:250 to about 500:1,from about 1:500 to about 250:1, from about 1:250 to about 250:1, fromabout 1:100 to about 250:1, from about 1:250 to about 100:1, from about1:100 to about 100:1, from about 1:100 to about 50:1, from about 1:50 toabout 100:1, from about 1:50 to about 50:1, from about 1:25 to about50:1, from about 1:50 to about 25:1, from about 1:25 to about 25:1, fromabout 1:10 to about 10:1, from about 1:1000 to about 250:1, from about1:1000 to about 100:1, from about 1:1000 to about 50:1, from about1:1000 to about 25:1, from about 1:1000 to about 10:1, from about 1:1000to about 5:1, from about 1:10 to about 1:20, from about 1:10 to about1:30, from about 1:10 to about 1:40, from about 1:10 to about 1:50, fromabout 1:10 to about 1:60, from about 1:10 to about 1:70, from about 1:10to about 1:80, from about 1:10 to about 1:90, from about 1:20 to about1:30, from about 1:20 to about 1:40, from about 1:20 to about 1:50, fromabout 1:20 to about 1:60, from about 1:20 to about 1:70, from about 1:20to about 1:80, from about 1:20 to about 1:90, from about 1:30 to about1:90, or any range therein.

In some embodiments, the composition comprises a ratio of a tannin andhydrogen peroxide, a phenylpropanoid and a hydrogen peroxide, a catechinand hydrogen peroxide, an epigallic acid and a hydrogen peroxide, or acombination thereof an of these phenolic compounds with hydrogenperoxide.

In some embodiments, the compositions include a stable hydrogen bondedcomplex between the phenolic compound and the reactive oxygen species.For example, a highly hydroxylated polyphenol compound can be combinedwith a high concentration of hydrogen peroxide, the combination leadingto binding the hydrogen peroxide to the phenolic compound to produce thebinding system. The binding system can be intended for dilution in wateror a solid excipient. One of skill will appreciate that such a complexcan be referred to as a polyphenol peroxysolvate, in some embodiments,when in a liquid form for storage or administration to a subject, and aphenolic perhydrate when in an anhydrous, or substantially anhydrous,form for storage or administration to a subject.

The compositions can be carried in a liquid, powder, capsule, tablet, orgas for administration to a subject. The selection of the phenoliccompound should take into consideration the manner in which the reactiveoxygen species will bind to the phenolic compound to form a stable, orsubstantially stable, binding pair. The binding pair can be consideredsubstantially stable where the reactive oxygen species retains all,most, or at least a predictable amount of oxidation strength for theuses and functions recited herein.

One of skill will appreciate that a phenolic compound can be derivatizedto introduce or enhance a desired function. The phenolic compound can bederivatized, for example, to increase it's functionality for binding tothe reactive oxygen species, maintaining stability or miscibility in acarrier, or binding to a target site, using any method known to one ofskill. In some embodiments, the phenolic compound can be bound to apolyol, pegylated, attached to a saccharide, or attached to glucose, forexample.

Moreover, one of skill will appreciate that the compositions should, insome embodiments, be produced free of compounds that can lead todegradation of the otherwise stable, or substantially stable,combinations. As such, in some embodiments, the compositions comprisesolutes that are substantially free of transition metals, metal ions,heavy metals, oxidoreductase enzymes, other strong oxidizers, reactivehalogen compounds, hydrogen halides, and other compounds that can causea decomposition of the reactive oxygen species, or its disassociationfrom the phenolic compound with which it forms a binding pair.

The compositions can be made using ingredients from commerciallyavailable chemical providers, or they can be made directly from whole,plant extracts, for example, water extracts or alcohol extracts.

A Commercially Available Source of the Phenolic Component

Commercially available chemical providers, for example Sigma-Aldrich,can provide phenolic and polyphenolic chemicals for use with the methodsof treatment taught herein. In the example set forth below, (i) gallicacid (a model polyphenol building block) is combined with hydrogenperoxide; and, (ii) tannic acid (a model polyphenol component) iscombined with hydrogen peroxide. Both gallic acid and tannic acid arecommercially available from Sigma-Aldrich. One of skill will appreciatethat a wide variety of polyphenolics are commercially available.

A Whole, Plant Extract as a Source of the Phenolic Component

The method of obtaining the phenolic component, e.g, the polyphenolcomponent, from a plant tissue can be produced using the followingprocess:

-   -   i. Harvest plant tissue comprising a polyphenol component, for        example, the polyphenol comprising a tannin. It is desirable to        harvest while minimizing physical damage to the plant tissue.        For example, whole leaf extractions can be performed to avoid        physical damage to the leaves, but it may be desirable to reduce        the size of the leaves by cutting them, for example, to increase        the speed and yield of the extraction in some embodiments.    -   ii. Denaturing all, or substantially all, of the oxidoreductase        enzymes in the plant. This can be done through drying, for        example, using heating in the range of about 60° C. to about        150° C., or a combination of such heating and dessication.        Alcohols can also be used to denature the enzymes.    -   iii. Extracting the polyphenols from the plant tissue using a        suitable solvent including, but not limited to, water or an        alcohol. Water extractions have been used in this example. Since        we're after water soluble plant materials, a simple water        extraction is sufficient to provide the plant extract containing        polyphenols for the compositions.

The plant extraction procedures are simple, although they can bemodified for efficiency in product yield and activity. Althoughinefficient, the simplest extraction procedure, for example, would be tomerely harvest the plant tissue, denature the endogeneous enzymes, andsoak the tissue in water to isolate the water soluble extract of theplant tissue. Another simple extraction method would be to harvest theplant tissue, and isolate the water soluble extract of the tissue inwater at temperatures greater than about 80° C. to steam. An evensimpler process would not include denaturing the enzymes, but thestability and activity of the extract in the composition suffersgreatly. Additional steps can be added, however, to increase theefficiency of the extraction, although such steps are not required. Forexample, the harvesting can include cutting into as large of pieces aspractical to the size of the plant to preserve the metabolic activity inthe plant tissue can be done. The plant tissue can be pulverized afterdenaturing the enzymes, and the water can be heated at temperaturesranging from about 25° C. to about 100° C., from about 30° C. to about95° C., from about 35° C. to about 90° C., from about 40° C. to about85° C., from about 45° C. to about 80° C., from about 45° C. to about75° C., from about 45° C. to about 70° C., from about 45° C. to about65° C., or any amount or range therein in increments of 1° C., to makethe process of extraction more efficient.

In some embodiments, the endogeneous enzymes include a catalase orperoxidase that is at least substantially inactivated. In someembodiments, the endogeneous enzymes can be inactivated through heating,cooling, boiling, freezing, dessicating, freezing and thawing cycles,blanching, or a combination thereof. In some embodiments, theendogeneous enzymes can be inactivated using a process that includesallowing natural degradation over time, adding at least 1% salt,radiating, or adding an exogeneous chemical enzymatic inhibitor.

In some embodiments, the plant extract is produced from a processcomprising: harvesting the plant tissue; at least partially inactivatingan endogeneous enzyme; optionally reducing particle size of the planttissue through cutting, avulsing, or pulverizing; creating the extractedcomponent through a process that includes combining the plant tissuewith water or alcohol for an effective time and at an effectivetemperature; optionally removing particles from the mixture; and, addingthe reactive oxygen species to the effective, or otherwise desired,amount.

In some embodiments, the water soluble plant extract can then beoptionally filtered, for example, using a filter, for example a 5 umfilter in some embodiments, and hydrogen peroxide can then be added tothe filtered extract to a concentration of 1% by weight of the totalcomposition. In some embodiments, the hydrogen peroxide can be added tothe extract in an amount ranging from about 0.01% to about 10% by weightof the total composition. Increasing the concentration of hydrogenperoxide added has been observed to increase the potency and stabilityof the resulting compositions.

After combining the reactive oxygen species with the polyphenolcomponent, the free reactive oxygen species in the compositions can beleft in the composition, or it can be removed using an enzyme, catalyst,or reducing agent. In this example, the reactive oxygen species ishydrogen peroxide, and the free hydrogen peroxide can be removed fromthe composition in a subsequent step contacting the free hydrogenperoxide with a hydrogen peroxide degrading enzyme, such catalase; acatalyst such as manganese dioxide, platinum, iron, or copper; or, areducing agent such as ferric chloride, copper sulfate, or sodiumhypochlorite. In some embodiments, the composition having the freehydrogen peroxide can be contacted with a metal catalyst or catalasebound to a solid non-soluble substrate. In some embodiments, the solidsubstrate can be a bead column or screen, for example. Likewise, thecatalysts and reducing agents can be used in a similar manner to removethe free hydrogen peroxide, or any other free reactive oxygen species.

As such, the concentration of free reactive oxygen species, such as freehydrogen peroxide, remaining in the composition can range from about 0to about 10% based on total dry weight of the composition. Moreover, insome embodiments, the total hydrogen peroxide concentration can rangefrom about 0.001% to about 1%, from about 0.001% to about 0.1%, fromabout 0.01% to about 0.05%, from about 0.005% to about 5%, from about0.007% to about 2%, from about 0.01% to about 5%, from about 0.05% toabout 5%, from about 0.1% to about 5%, from about 0.2% to about 4.5%,from about 0.3% to about 4%, from about 0.4% to about 3.5%, from about0.5% to about 3%, from about 0.6% to about 2.5%, from about 0.7% toabout 2%, from about 0.001% to about 1.5%, about 1%, or any amount orrange therein in increments of 0.001%. And, it should be appreciatedthat the concentration of free hydrogen peroxide, for example, can alsobe reduced, or further reduced, by dilution of the composition invarious commercial formulations.

Moreover, precipitates of protein or other impurities can form at thispoint and can optionally be removed by additional filtration, and weoften filter after we allow the solution to react for about an hour.Although not necessary, additional reactive oxygen species can be addedto ensure complete saturation of hydrogen peroxide on the binding sitesof the polyphenols in the extract. In this example, hydrogen peroxidewas used as the reactive oxygen species, keeping track of the totalhydrogen peroxide concentration.

The plant extract is combined with the reactive oxygen species, and thesolution can be allowed to react for a period of time ranging from about10 minutes to about 72 hours, in some embodiments, before diluting thecomposition to a desired concentration. In some embodiments, thesolution can be allowed to react for a period of time ranging from about1 minute to about 96 hours, from about 5 minutes to about 48 hours, fromabout 10 minutes to about 36 hours, from about 10 minutes to about 24hours, from about 10 minutes to about 12 hours, from about 10 minutes toabout 8 hours, or from about 10 minutes to about 1 hour, or any rangetherein in increments of 1 minute. In this example, the extracts wereallowed to react with the hydrogen peroxide for a minimum of 2 hours.The dilution can be desirable, for example, (i) to control theconcentration of the composition in solution, and/or (ii) to acceleratedegradation of the unbound reactive oxygen species to limit thecomposition to having no, or substantially no, free reactive oxygenspecies. In this example, the hydrogen peroxide is more susceptible todegradation when free in solution, and one of skill will appreciate thatthe degradation will increase in rate when the composition is diluted.

In some embodiments, dry compositions are provided. For example, thesystem can be in the form of a powder, pill, tablet, capsule, or asseparate dry components for mixing into a liquid form. In theseembodiments, both the phenolic compound and the reactive oxygen speciesare in a dry form either before or after creation of the binding pair,and the binding system can be used in the dry form, or converted to aliquid form, for any of the uses taught herein. The advantages of thedry compositions can include, for example, the ease of storage andtransport. In some embodiments, the binding systems, whether in liquidor dry form, can be combined with vitamins, electrolytes, and/or othernutrients in either liquid or dry form. The dry form of the bindingsystem can be manufactured using any drying process known to one ofskill, such as solvent exchange, vacuum drying, critical point drying,heating, dessication, or a combination thereof. In some embodiments, thephenolic compound is dried as a single component. In some embodiments,the binding pair is formed, and the binding pair is dried together. And,in some embodiments, the reactive oxygen species can be, independently,in any dry form known to one of skill, such as the dry forms taughtherein. In embodiments having the reactive oxygen species in anindependent dry form, the dry phenolic compound and the dry reactiveoxygen species can be combined in a polar solvent, for example, tocreate the binding pair prior to use.

Methods of Using the Compositions

Methods of treating gastrointestinal spasms are provided. This caninclude reducing or eliminating abdominal pain, bloating, forcefuldefecation, forceful vomiting, defecation urgency, constipation, and/orincontinence. Causes of gastrointestinal cramping can range from mildconditions to serious conditions, such as food poisoning, constipation,gastroenteritis, viral infections, bacterial infections, lactoseintolerance, excessive flatulence and bloating, indigestion,diverticulitis, autoimmune disease, intestinal inflammation and evencolorectal cancer, adhesions, and the like. In some embodiments, stressand/or dehydration can even trigger gastrointestinal cramps, forexample.

The disorders treated can be self-induced. In some embodiments,gastrointestinal spasms can be self-induced through overindulging, suchas through overeating and/or overdrinking. In some embodiments,gastrointestinal spasms can be due to deficiencies, such as deficienciesin nutrition or hydration, for example. The compositions taught hereincan be used in treating such conditions, either alone or inco-administrations with nutritional therapy or rehydration therapies.The disorders might also be induced through environmental conditions,exercise, or socioeconomic conditions. In some embodiments, thecomposition can be co-administered with at least one other nutritionaland/or rehydrating agent for aiding recovery from a health imbalance, orto maintain a health balance. Examples of rehydrating agents caninclude, but are not limited to, GATORADE and other electrolyte drinks,oral rehydration solutions (ORSs) generally, new oral rehydrationsolution (N-ORS), SEURO ORAL, PEDIAONE, and PEDIALYTE. Examples ofnutritional supplements can include, but are not limited to, zincsulfate, salted rice water, salted yogurt-based drinks, and vegetable orchicken soup with salt. Such health imbalances can include, but is notlimited to, dehydration, malnutrition, electrolyte imbalance, vitamindeficiency, food hypersensitivities, stress induced diarrhea, abdominalcramping, and alcohol hangover, or a combination thereof. In someembodiments, the methods taught herein can further include theadministration of oral rehydrating or nutritional agents such as sodium,potassium, dextrose, fructose, glucose, magnesium, zinc, selenium,vitamin A, Vitamin D, Vitamin C, dietary fiber, and combinationsthereof. The amounts and ratios of the agents to the composition can besubstantially varied to provide prophylaxis, therapy or maintenance ofhealthful balance. Ratios of the compositions herein to the nutritionalagents or rehydration agents can range, for example, from about 1:100 toabout 100:1, from about 1:50 to about 50:1, from about 1:40 to about40:1, from about 1:30 to about 30:1, from about 1:20 to about 20:1, fromabout 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 toabout 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1.5 to about 1.5:1, about 1:1, or any range therein. Theratios can be based on volume:volume, mass:volume, volume:mass,mass:mass, or molar:molar. It should be appreciated that theconcentrations of the compositions taught herein can be the same ordifferent than the concentrations of the nutritional agents orrehydration agents. And, it should also be appreciated that theconcentrations and ratios of concentrations can be subjective to aparticular administration, such that they can be independently selectedaccording to the condition treated, objective sought, desired effect,and/or personal preference. The combinations can be administered underany regime taught herein for the administration of an agent orcombination of agents.

Irritable bowel syndrome (IBS) is a problem of particular interest andincludes, for example, chronic or frequent gastrointestinal spasms. IBSis often diagnosed as a set of these symptoms, such as diarrhea,constipation, and bloating, in addition to, perhaps, a measured foodsensitivity. The compositions taught herein, however, can generally beused for this and other medicinal purposes, as a health supplement, or anutritional composition. The compositions can provide a therapeuticand/or prophylactic effect in the treatment of a condition in a subject,particularly in the treatment of a gastrointestinal spasm. The targetedaction of the binding systems allows for the administration ofsurprisingly low effective doses of the phenolic compounds. As a result,the compositions also improve safety by substantially increasing theseparation between an effective dose and any toxic/side effects.

The terms “treat,” “treating,” and “treatment” can be usedinterchangeably and refer to the administering or application of thebinding systems taught herein, including such administration as a healthor nutritional supplement, and all administrations directed to theprevention, inhibition, amelioration of the symptoms, or cure of acondition taught herein. The terms “disease,” “condition,” “disorder,”and “ailment” can be used interchangeably in some embodiments. The term“subject” and “patient” can be used interchangeably and refer to ananimal such as a mammal including, but not limited to, non-primates suchas, for example, a cow, pig, horse, cat, dog, rat and mouse; andprimates such as, for example, a monkey or a human. As such, the terms“subject” and “patient” can also be applied to non-human biologicapplications including, but not limited to, veterinary, companionanimals, commercial livestock, aquaculture, and the like. Many of theapplications can include control environmental pathogens that are on orin plants, as well as places not necessarily in living hosts, such asthose that are in water and water systems, for example, as well as soil,air, and food for microbial control, alteration of surfacecharacteristics, or anywhere that can benefit from a supply of a stableoxidizer source.

In some embodiments, the composition includes (i) a phenolic compoundselected from the group consisting of condensed tannins, hydrolysabletannins, complex tannins, phlorotannins, psuedotannins, and derivativesthereof; and, (ii) hydrogen peroxide in a stable, or substantiallystable, non-covalent association.

In some embodiments, the compositions taught herein can be used toprotect, maintain, improve, or restore a digestive health of a subjectwhen administered orally in an effective amount. In some embodiments,the effectiveness can be measured by comparing to a control group thatdid not receive the binding system. And, in some embodiments, theeffectiveness can be measured according to a historical baseline for thesubject being treated. The binding systems can be used to prevent,inhibit, or ameliorate the symptoms associated with a loss of digestivetract homeostasis. In some embodiments, the binding systems can be usedto prevent, treat, ameliorate the symptoms of, or even cure, a chronicgastrointestinal condition. Such conditions can include, but are notlimited to, hyperacidity, colitis, irritable bowel syndrome, crohn'sdisease, necrotic enteritis, functional colonic diseases, malabsorption,a peptic ulcer, gastro-esophageal reflux disease, ulcerative colitis,and diverticulitis. In some embodiments, the binding systems can be usedto reduce mucosal tissue inflammation, dysfunction, or damage. Suchconditions can be induced, for example, by drug side effects,chemotherapy, dysbiosis, radiation, changes in normal flora,hyperimmunity, autoimmune reactions, immune deficiencies, nervousness,allergies, chemical irritation, and stress. In some embodiments, thebinding systems can be administered for selectively inhibiting thegrowth of gastrointestinal pathogens. It should be appreciated thatthere may be lesser inhibition of non-pathogenic strains, particularlycommon probiotic bacteria such as bifidobacteria and lactobacilli. And,in some embodiments, administration of the binding systems can produceshort term immune modulation effects as well as potentially change thechronic expression of the activating enzymes associated with someconditions with longer term use of the binding systems.

In some embodiments, the symptoms of a gastrointestinal condition caninclude, for example, diarrhea, dehydration, malnutrition, constipation,nausea, and/or cramping. And, in some embodiments, the symptoms of agastrointestinal condition can be temporary and include acid irritation,indigestion, bloating, cramps, spasmodic peristalsis, diarrhea, andconstipation. Administering the binding systems for the treatment and/ormanagement of gastrointestinal conditions can be considered anutritional or health supplement, in some embodiments. In some suchembodiments, for example, the binding pair can be administered toprevent, inhibit, or ameliorate the effect, infectivity, and virulenceof pathogens including bacteria, virus, fungi, yeast, prions, protozoaand parasites in a subject orally taking an effective amount of thesupplement.

As described herein, the binding systems can be used in a method oftreating acute diarrhea in a subject. In some embodiments, the methodscomprise orally administering an effective amount of a binding systemtaught herein to the subject. The binding system can prevent, inhibit,or ameliorate a symptom of acute diarrhea in the subject when comparedto a second subject in a control group in which the binding system wasnot administered. In some embodiments, the symptom is selected from thegroup consisting of a stool score, heartburn, indigestion, urgency ofdefecation, nausea, vomiting, stomach pain, and bloating.

As described herein, the binding systems can be used in a method oftreating irritable bowel syndrome in a subject. In some embodiments, themethod comprises orally administering an effective amount of a bindingsystem taught herein to the subject. The binding system can prevent,inhibit, or ameliorate the symptoms of irritable bowel syndrome in thesubject when compared to a second subject in a control group in whichthe binding system was not administered. In some embodiments, thesymptom is selected from the group consisting of a stool score,heartburn, indigestion, urgency of defecation, nausea, vomiting, stomachpain, and bloating.

As described herein, the binding systems can be used in a method oftreating an inflammatory bowel disease in a subject. In someembodiments, the method comprises orally administering an effectiveamount of a binding system taught herein to the subject. The bindingsystem can prevent, inhibit, or ameliorate the symptoms of inflammatorybowel disease in the subject when compared to a second subject in acontrol group in which the binding system was not administered. In someembodiments, the symptom is selected from the group consisting of astool score, heartburn, indigestion, urgency of defecation, nausea,vomiting, stomach pain, and bloating.

As described herein, the binding systems can be used in a method oftreating food poisoning in a subject. In some embodiments, the methodcomprises orally administering an effective amount of a binding systemtaught herein to the subject. The binding system can prevent, inhibit,or ameliorate the symptoms of food poisoning in the subject whencompared to a second subject in a control group in which the bindingsystem was not administered. In some embodiments, the symptom isselected from the group consisting of a stool score, heartburn,indigestion, urgency of defecation, nausea, vomiting, stomach pain, andbloating.

Methods of Administering the Compositions

The terms “administration” or “administering” can be used to refer to amethod of incorporating a composition into the cells or tissues of asubject, either in vivo or ex vivo to test the activity of a system, aswell as to diagnose, prevent, treat, or ameliorate a symptom of adisease. In one example, a compound can be administered to a subject invivo using any means of administration taught herein. In anotherexample, a compound can be administered ex vivo by combining thecompound with cell tissue from the subject for purposes that include,but are not limited to, assays for determining utility and efficacy of acomposition. And, of course, the systems can be used in vitro to testtheir stability, activity, toxicity, efficacy, and the like. When thecompound is incorporated in the subject in combination with one oractive agents, the terms “administration” or “administering” can includesequential or concurrent incorporation of the compound with the otheragents such as, for example, any agent described above. A pharmaceuticalcomposition of the invention can be formulated, in some embodiments, tobe compatible with its intended route of administration.

Any administration vehicle known to one of skill to be suitable foradministration of the compounds, compositions, and formulations taughtherein can be used. A “vehicle” can refer to, for example, a diluent,excipient or carrier with which a compound is administered to a subject.A “pharmaceutically acceptable carrier” is a diluent, adjuvant,excipient, or vehicle with which the composition is administered. Acarrier is pharmaceutically acceptable after approval by a state orfederal regulatory agency or listing in the U.S. PharmacopeialConvention or other generally recognized sources for use in subjects.The pharmaceutical carriers include any and all physiologicallycompatible solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and thelike. Examples of pharmaceutical carriers include, but are not limitedto, sterile liquids, such as water, oils and lipids such as, forexample, phospholipids and glycolipids. These sterile liquids include,but are not limited to, those derived from petroleum, animal, vegetableor synthetic origin such as, for example, peanut oil, soybean oil,mineral oil, sesame oil, and the like. Suitable pharmaceuticalexcipients include, but are not limited to, starch, sugars, inertpolymers, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanol,and the like. The composition can also contain minor amounts of wettingagents, emulsifying agents, pH buffering agents, or a combinationthereof. The compositions can take the form of solutions, suspensions,emulsion, tablets, pills, capsules, powders, sustained-releaseformulations and the like. Oral formulations can include standardcarriers such as, for example, pharmaceutical grades mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate, and the like. See Martin, E.W. Remington's PharmaceuticalSciences. Supplementary active compounds can also be incorporated intothe compositions. In some embodiments, the carrier can be a solvent ordispersion medium including, but not limited to, water; ethanol; apolyol such as for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like; and, combinations thereof. The properfluidity can be maintained in a variety of ways such as, for example,using a coating such as lecithin, maintaining a required particle sizein dispersions, and using surfactants.

The compositions can be administered to a subject orally or rectally,for example, in the treatment of a gastrointestinal spasm. Oraladministration can include digestive tract, buccal, sublingual, andsublabial, and a carrier such as a solid or liquid can be used. A solidcan include, for example, a pill, capsule, tablet, or time-releasetechnology in some embodiments; and, for buccal or sublingual, a solidcan include an orally disintegrating tablet, a film, a lollipop, alozenge, or chewing gum; and, a liquid can include a mouthwash, atoothpaste, an ointment, or an oral spray. A liquid can include, forexample, a solution, soft gel, suspension, emulsion, syrup, elixir,tincture, or a hydrogel.

Tablets, pills, capsules, troches liquids and the like may also containbinders, excipients, disintegrating agent, lubricants, glidants,chelating agents, buffers, tonicity modifiers, surfactants, sweeteningagents, and flavoring agents. Some examples of binders includemicrocrystalline cellulose, gum tragacanth or gelatin. Some examples ofexcipients include starch or maltodextrin. Some examples ofdisintegrating agents include alginic acid, corn starch and the like.Some examples of lubricants include magnesium stearate or potassiumstearate. An example of a chelating agent is EDTA. Some examples ofbuffers are acetates, citrates or phosphates. Some examples of tonicitymodifiers include sodium chloride and dextrose. Some examples ofsurfactants for micellation or increasing cell permeation includecoconut soap, anionic, cationic or ethoxylate detergents. An example ofa glidant is colloidal silicon dioxide. Some examples of sweeteningagents include sucrose, saccharin and the like. Some examples offlavoring agents include peppermint, chamomile, orange flavoring and thelike. It should be appreciated that the materials used in preparingthese various compositions should be pharmaceutically pure and non-toxicin the amounts used

Rectal administrations can be made using any method known to one ofskill. For example, a suppository formulation can be prepared by heatingglycerin to about 120° C., combining the binding system with the heatedglycerin, mixing the combination, adding purified water to a desiredconsistency, and pouring the desired consistency into a mold to form thesuppository.

The compositions may be administered as suspensions or emulsions.Lipophilic solvents or vehicles include, but are not limited to, fattyoils such as, for example, sesame oil; synthetic fatty acid esters, suchas ethyl oleate or triglycerides; and liposomes. Suspensions that can beused for injection may also contain substances that increase theviscosity of the suspension such as, for example, sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, a suspension may containstabilizers or agents that increase the solubility of the compounds andallow for preparation of highly concentrated solutions. In someembodiments, an administration, such as an oral or rectaladministration, for example, may include liposomes. In some embodiments,the liposome may assist in a targeted delivery system. The liposomes canbe designed, for example, to bind to a target protein and be taken upselectively by the cell expressing the target protein.

In some embodiments, isotonic agents can be used such as, for example,sugars; polyalcohols that include, but are not limited to, mannitol,sorbitol, glycerol, and combinations thereof; and sodium chloride.Sustained absorption characteristics can be introduced into thecompositions by including agents that delay absorption such as, forexample, monostearate salts, gelatin, and slow release polymers.Carriers can be used to protect against rapid release, and such carriersinclude, but are not limited to, controlled release formulations inimplants and microencapsulated delivery systems. Biodegradable andbiocompatible polymers can be used such as, for example, ethylene vinylacetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters,polylactic acid, polycaprolactone, polyglycolic copolymer, and the like.Such formulations can generally be prepared using methods known to oneof skill in the art.

In some embodiments, the composition is administered in a sustainedrelease formulation, and the formulation can include one or more agentsin addition to the composition. In some embodiments, the sustainedrelease formulations can reduce the dosage and/or frequency of theadministrations of such agents to a subject. In some embodiments, anexogenous catalyst or enzyme is introduced to a target and one or moreof the reactive oxygen species, phenolic compound, or the exogeneouscatalyst or enzyme are segregated by encapsulation or micellation todelay the bioactivation until target site is reached by all components.

One of skill understands that the amount of the agents administered canvary according to factors such as, for example, the type of disease,age, sex, and weight of the subject, as well as the method ofadministration. For example, an administration can call forsubstantially different amounts to be effective. Dosage regimens mayalso be adjusted to optimize a therapeutic response. In someembodiments, a single bolus may be administered; several divided dosesmay be administered over time; the dose may be proportionally reduced orincreased; or, any combination thereof, as indicated by the exigenciesof the therapeutic situation and factors known one of skill in the art.It is to be noted that dosage values may vary with the severity of thecondition to be alleviated, as well as whether the administration isprophylactic, such that the condition has not actually onset or producedsymptoms. Dosage regimens may be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthe dosage ranges set forth herein are exemplary only and do not limitthe dosage ranges that may be selected by medical practitioners. Thecompounds can be administered in dosage units. The term “dosage unit”can refer to discrete, predetermined quantities of a compound that canbe administered as unitary dosages to a subject. A predeterminedquantity of active compound can be selected to produce a desiredtherapeutic effect and can be administered with a pharmaceuticallyacceptable carrier. The predetermined quantity in each unit dosage candepend on factors that include, but are not limited to, (a) the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and (b) the limitations inherent in the art ofcreating and administering such dosage units.

An “effective amount” of a compound can be used to describe atherapeutically effective amount or a prophylactically effective amount.An effective amount can also be an amount that ameliorates the symptomsof a disease. A “therapeutically effective amount” can refer to anamount that is effective at the dosages and periods of time necessary toachieve a desired therapeutic result and may also refer to an amount ofactive compound, prodrug or pharmaceutical agent that elicits anybiological or medicinal response in a tissue, system, or subject that issought by a researcher, veterinarian, medical doctor or other clinicianthat may be part of a treatment plan leading to a desired effect. Insome embodiments, the therapeutically effective amount should beadministered in an amount sufficient to result in amelioration of one ormore symptoms of a disorder, prevention of the advancement of adisorder, or regression of a disorder. In some embodiments, for example,a therapeutically effective amount can refer to the amount of an agentthat provides a measurable response of at least 5%, at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 100% of a desired action of thecomposition.

In some embodiments, the desired action of the composition is relief ofa gastrointestinal spasm. The relief can include, for example, reducingor eliminating abdominal pain, bloating, forceful defecation, forcefulvomiting, defecation urgency, constipation, and/or incontinence. Inthese embodiments, at least 10% relief can be obtained in a time rangingfrom 1 minute to 24 hours, from about 5 minutes to about 18 hours, fromabout 10 minutes to about 12 hours, from about 20 minutes to about 8hours, from about 30 minutes to about 6 hours, from about 1 hours toabout 4 hours, from about 2 hours to about 10 hours, from about 3 hoursto about 9 hours, or any range or amount therein in increments of 5minutes.

A “prophylactically effective amount” can refer to an amount that iseffective at the dosages and periods of time necessary to achieve adesired prophylactic result, such as prevent the onset of aninflammation, allergy, nausea, diarrhea, infection, and the like.Typically, a prophylactic dose is used in a subject prior to the onsetof a disease, or at an early stage of the onset of a disease, to preventor inhibit onset of the disease or symptoms of the disease. Aprophylactically effective amount may be less than, greater than, orequal to a therapeutically effective amount.

In some embodiments, a therapeutically or prophylactically effectiveamount of a composition may range in concentration from about 0.01 nM toabout 0.10 M; from about 0.01 nM to about 0.5 M; from about 0.1 nM toabout 150 nM; from about 0.1 nM to about 500 μM; from about 0.1 nM toabout 1000 nM, 0.001 μM to about 0.10 M; from about 0.001 μM to about0.5 M; from about 0.01 μM to about 150 μM; from about 0.01 μM to about500 μM; from about 0.01 μM to about 1000 nM, or any range therein. Insome embodiments, the compositions may be administered in an amountranging from about 0.005 mg/kg to about 100 mg/kg; from about 0.005mg/kg to about 400 mg/kg; from about 0.01 mg/kg to about 300 mg/kg; fromabout 0.01 mg/kg to about 250 mg/kg; from about 0.1 mg/kg to about 200mg/kg; from about 0.2 mg/kg to about 150 mg/kg; from about 0.4 mg/kg toabout 120 mg/kg; from about 0.15 mg/kg to about 100 mg/kg, from about0.15 mg/kg to about 50 mg/kg, from about 0.5 mg/kg to about 10 mg/kg, orany range therein, wherein a human subject is often assumed to averageabout 70 kg.

The amount of the composition administered may vary widely depending onthe type of formulation, size of a unit dosage, kind of excipients, andother factors well known to those of ordinary skill in the art. Aformulation may comprise, for example, an amount of the compositionranging from about 0.0001% to about 6% (w/w), from about 0.01% to about1%, from about 0.1% to about 0.8%, or any range therein, with theremainder comprising the excipient or excipients. In some embodiments,the compositions can be administered, for example, in an amount ofranging from about 0.1 μg/kg to about 1 mg/kg, from about 0.5 μg/kg toabout 500 μg/kg, from about 1 μg/kg to about 250 μg/kg, from about 1μg/kg to about 100 μg/kg from about 1 μg/kg to about 50 μg/kg, or anyrange therein. One of skill can readily select the frequency andduration of each administration. For example, depending on thegastrointestinal disorder treated, whether a prophylactic treatment or atreatment of an existing disorder, variables such as the age and size ofthe subject can be considered, as well as the source and type of thepolyphenol component and the intensity of the symptoms. In theseembodiments, the compositions can be administered orally in daily dosesranging from about 5 μg to about 5000 μg dry weight, for example. Insuch embodiments, the compositions can be administered orally in amountsranging from about 5 μg to about 5000 μg, from about 10 μg to about 4000μg, from about 20 μg to about 3000 μg, from about 50 μg to about 2000μg, from about 100 μg to about 1000 μg, from about 250 μg to about 500μg, or any range therein, in dry weight. In some embodiments, thecompositions can be administered orally in daily doses of about 100 μg,about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg,about 700 μg, about 800 μg, about 900 μg, about 1000 μg, about 2000 μg,about 3000 μg, about 4000 μg, about 5000 μg, about 6000 μg, about 7000μg, about 8000 μg, about 9000 μg, or any range therein in increments of50 μg dry weight.

In some embodiments, the composition can be administered in conjunctionwith at least one other therapeutic agent for the condition beingtreated. The amounts of the agents can be reduced, even substantially,such that the amount of the agent or agents desired is reduced to theextent that a significant response is observed from the subject. Asignificant response can include, but is not limited to, a reduction orelimination of nausea, a visible increase in tolerance, a fasterresponse to the treatment, a more selective response to the treatment,or a combination thereof. In some embodiments, the methods taught hereincan further include the administration of an antibiotic, an anti-emetic,an anticholinergic, an antispasmodic, or an anticancer agent.

Antibiotics can include, for example, aminoglycosides, ansamycins,carbacephem, carbapenems, cephalosporins (first through fifthgeneration), glycopeptides, lincosamides, macrolides, monobactams,penicillins, penicillin combinations, polypeptides, quinolones,sulfonamides, tetracyclines, and drugs against mycobacteria. In someembodiments, the antibiotic is selected from the group consisting ofnatural penicillin, cephalosporin, amoxicillin, ampicillin, clavamox,polymyxin, tetracycline, chlortetracycline, doxycycline,chloramphenicol, erythromycin, oleandomycin, streptomycin, gentamicin,kanamycin, tombramycin, nalidixic acid, rifamycin, rifampicin,prontisil, gantrisin, trimethoprim, isoniazid, para-aminosalicylic acid,and ethambutol. One of skill will appreciate that subgroups of thisgroup can be desired in some embodiments. Anti-emetics can include, forexample, anticholinergic agents, antidopaminergic agents, 5-HT₃antagonists, H1 antihistamines, cannabinoids, corticosteroids, andbenzodiazepines. In some embodiments, the anti-emetics can be selectedfrom the group consisting of benzodiazepines such as diazepam orlorazepam; 5-HT₃ receptor antagonists such as ondansetron, tropisetron,granisetron, and dolasetron. Antispasmodics can include, for example,anticholinergics such as dicyclomine and hyoscyamine, as well asmebeverine and papaverine, for example. Anticancer agents can include,for example, alkylating agents, antimetabolites, anthracyclines, plantalkaloids, topoisomerase inhibitors, and other antitumor agents. One ofskill will appreciate that the agents listed above can be used alone, orin combination, in some embodiments. For example, chemotherapy andanti-emetics can be administered together. And, anti-emetics can beadministered together, such as a combination of corticosteroids and asecond anti-emetic such as an antihistamine, anticholinergic,benzodiazepine, cannabinoid, or an anti-dopaminergic agent.

Combinations therapies can be administered, for example, for 30 minutes,1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks,3 weeks, 4 weeks, 6 weeks, 3 months, 6 months 1 year, any combinationthereof, or any amount of time considered necessary by one of skill. Theagents can be administered concomitantly, sequentially, or cyclically toa subject. Cycling therapy involves the administering a first agent fora predetermined period of time, administering a second agent or therapyfor a second predetermined period of time, and repeating this cyclingfor any desired purpose such as, for example, to enhance the efficacy ofthe treatment. The agents can also be administered concurrently. Theterm “concurrently” is not limited to the administration of agents atexactly the same time, but rather means that the agents can beadministered in a sequence and time interval such that the agents canwork together to provide additional benefit. Each agent can beadministered separately or together in any appropriate form using anyappropriate means of administering the agent or agents.

The compositions taught herein can be used in co-administrations withnutritional therapy or rehydration therapies. In some embodiments, thecomposition can be co-administered with at least one other nutritionaland/or rehydrating agent for aiding recovery from a health imbalance, orto maintain a health balance. Examples of rehydrating agents caninclude, but are not limited to, GATORADE and other electrolyte drinks,oral rehydration solutions (ORSs) generally, new oral rehydrationsolution (N-ORS), SEURO ORAL, PEDIAONE, and PEDIALYTE. Examples ofnutritional supplements can include, but are not limited to, zincsulfate, salted rice water, salted yogurt-based drinks, and vegetable orchicken soup with salt. Such health imbalances can include, but is notlimited to, dehydration, malnutrition, electrolyte imbalance, vitamindeficiency, food hypersensitivities, stress induced diarrhea, abdominalcramping, and alcohol hangover, or a combination thereof. In someembodiments, the methods taught herein can further include theadministration of oral rehydrating or nutritional agents such as sodium,potassium, dextrose, fructose, glucose, magnesium, zinc, selenium,vitamin A, Vitamin D, Vitamin C, dietary fiber, and combinationsthereof. The amounts and ratios of the agents to the composition can besubstantially varied to provide prophylaxis, therapy or maintenance ofhealthful balance. Ratios of the compositions herein to the nutritionalagents or rehydration agents can range, for example, from about 1:100 toabout 100:1, from about 1:50 to about 50:1, from about 1:40 to about40:1, from about 1:30 to about 30:1, from about 1:20 to about 20:1, fromabout 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:4 toabout 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1.5 to about 1.5:1, about 1:1, or any range therein. Theratios can be based on volume:volume, mass:volume, volume:mass,mass:mass, or molar:molar. It should be appreciated that theconcentrations of the compositions taught herein can be the same ordifferent than the concentrations of the nutritional agents orrehydration agents. And, it should also be appreciated that theconcentrations and ratios of concentrations can be subjective to aparticular administration, such that they can be independently selectedaccording to the condition treated, objective sought, desired effect,and/or personal preference. The combinations can be administered underany regime taught herein for the administration of an agent orcombination of agents.

Articles of Manufacture

Articles of manufacture that encompass finished, packaged and labelledproducts are provided. The articles of manufacture include theappropriate unit dosage form in an appropriate vessel or container suchas, for example, a glass vial or other container that is hermeticallysealed. In the case of dosage forms suitable for oral administration,the active ingredient, e.g. one or more agents including a dosage formtaught herein, may be suitable for administration orally, rectally, orthe like.

As with any such product, the packaging material and container aredesigned to protect the stability of the product during storage andshipment. In addition, the articles of manufacture can includeinstructions for use or other information material that can advise theuser such as, for example, a physician, technician or patient, regardinghow to properly administer the composition as a prophylactic,therapeutic, or ameliorative treatment of the disease of concern. Insome embodiments, instructions can indicate or suggest a dosing regimenthat includes, but is not limited to, actual doses and monitoringprocedures.

In some embodiments, the articles of manufacture can comprise one ormore packaging materials such as, for example, a box, bottle, tube,vial, container, sprayer, insufflator, intravenous (I.V.) bag, envelope,and the like; and at least one unit dosage form of an agent comprisingan extract taught herein within the packaging material. There can be afirst composition comprising at least one unit dosage form of an agentcomprising a binding system as taught herein within the packagingmaterial, and optionally, a second composition comprising a second agentsuch as, for example, any other bioactive agent that may be administeredin combination with the binding system, or any prodrugs, codrugs,metabolites, analogs, homologues, congeners, derivatives, salts,solvates, and combinations thereof. In some embodiments, the articles ofmanufacture may also include instructions for using the composition as adiagnostic, prophylactic, therapeutic, or ameliorative treatment for thecondition of concern. In some embodiments, the instructions can includeinformational material indicating how to administer the systems for aparticular use or range of uses, as well as how to monitor the subjectfor positive and/or negative responses to the systems.

In some embodiments, the article of manufacture can include asubstantially anhydrous binding system. For example, a kit can beassembled which includes the anhydrous binding system comprising ananhydrous tannin with instructions combining the tannin with and ananhydrous reactive species generating component that forms atherapeutically, prophylactically, or nutritionally useful compositionupon hydration.

Kits for the treatment of gastrointestinal spasms are provided herein.In these embodiments, the kits can include the polyphenol componentand/or the reactive oxygen species in a wet or dry form. Optionally, thekits can include instructions for use in treating a subject. Theinstructions can include, for example, instructions on diluting thecomposition to a desired concentration and administration according tosuggested dilution factors on the basis of ages and weights of subjects,as well as known conditions and target sites. The suggested dilutionfactors can be selected from the ranges taught herein. In someembodiments, the kits comprise a dry, stable form of the compositioncomponents. For example, the kits can comprise a dry form of apolyphenol component, such as one polyphenol, a combination ofpolyphenols, or an extract of a plant tissue having polyphenols.Moreover, the kits can also comprise a dry form of a hydrogen peroxidegenerating material that functions to generate an effective amount of anexogeneous reactive oxygen species, wherein the reactive oxygen speciesincludes a component selected from the group consisting of hydrogenperoxide, superoxide anion, singlet oxygen, and a hydroxyl radical. Inthese embodiments, the composition can be at least substantially free ofactive endogeneous oxidative enzymes and catalytic substances that causedegradation of the composition.

Example 1 Making and Testing an Antispasmodic Composition

This experiment includes the use of gallic acid, tannic acid, apomegranate husk extract, and a green tea extract.

Measuring the Amount of Hydrogen Peroxide that Remains Bound to thePolyphenol

One of skill knows that hydrogen peroxide does not exist in a pure,solid form under normal conditions, for example, ambient conditions.However, this example shows that the hydrogen peroxide can exist in dryform when in association with the model compounds and plant extracts,and the compositions have been isolated in a dry form as proof.Art-recognized procedures, such as those set-forth at least in U.S. Pat.Nos. 3,860,694; 3,864,454; 4,171,280; and 4,966,762, were used as aguide for this study.

The model compounds were used to show that the compounds includehydrogen peroxide, the reactive oxygen species component, in arelatively stable association with the polyphenol component. Asdiscussed, one of skill will appreciate that hydrogen peroxide in a freeform, for example, would otherwise quickly degrade. The polyphenols wereprovided from model compounds or plant extracts. A dry form of thecompositions was made between (i) gallic acid (a model polyphenolbuilding block from Sigma-Aldrich) and hydrogen peroxide; (ii) tannicacid (a model polyphenol component from Sigma-Aldrich) and hydrogenperoxide; (iii) pomegranate husk extract and hydrogen peroxide; and,(iv) green tea extract and hydrogen peroxide, using the procedurestaught herein, including:

-   -   i. adding a solution of 35% hydrogen peroxide slowly into each        of the gallic acid powder, tannic powder, pomegranate husk        extract powder, or green tea extract powder. The adding is done        in a glass dish or beaker at 45-65° C. under constant, gentle        mixing;    -   ii. creating a dry form of the composition by continuing the        heating under the constant, gentle mixing until fine dry        granules or hard amorphous chunks form;    -   iii. crushing the granules or chunks into a powder, which is the        dry form; dissolving the powder into water, knowing that the dry        forms will not have stable, free hydrogen peroxide, such that        the dissolved powder will carry only the stabilized hydrogen        peroxide associated with the model compounds or extracts; and,    -   iv. measuring the total hydrogen peroxide concentration        associated with the model compounds or extracts in the dry form.

The hydrogen peroxide concentration measurements were taken usingstandard methods to determine the amount of hydrogen peroxide that boundto the model compounds or extracts in the dry form. It was found that(i) about 3.0% hydrogen peroxide bound to the gallic acid (a modelpolyphenol building block) by total dry wt; (ii) about 2.5% hydrogenperoxide bound to the tannic acid (a model polyphenol component) bytotal dry wt; (iii) about 1.8% hydrogen peroxide bound to thepomegranate husk extract by total dry wt; and, (iv) about 2.0% hydrogenperoxide bound to the green tea extract by total dry wt. To measure thehydrogen peroxide levels, a standard, WATERWORKS peroxide test stripmethod was used having a test sensitivity of 0.5, 2, 5, 10, 25, 50, 100ppm, available from Industrial Test Systems, Inc., Rock Hill, S.C.29730.

FIGS. 1A-1H are photographs of the dry forms of (A) gallic acid (a modelpolyphenol building block) bound to hydrogen peroxide; (B) gallic acidalone; (C) tannic acid (a model polyphenol) bound to hydrogen peroxide;(D) tannic acid alone; (E) pomegranate husk extract bound to hydrogenperoxide; (F) pomegranate husk extract alone; (G) green tea extractbound to hydrogen peroxide; and (H) green tea extract alone, accordingto some embodiments. As can be seen, the dry compositions exist and docontain a stable amount of hydrogen peroxide in an amount ranging fromabout 1.8% to about 3.0%, indicating the stabilizing association betweenthe combined model compounds and extracts with the hydrogen peroxide.One of skill will appreciate that, surprisingly, the compositionscontain a substantial amount of a stabilized hydrogen peroxide that iscarried with the model compounds or extracts as a dry form.

The Stability of the Hydrogen Peroxide in the Combination is Greater inan Aqueous Solution than the Stability of the Hydrogen Peroxide Alone inthe Aqueous Solution

This method tests the stability of the hydrogen peroxide in thecombination. The testing methods used follow the standard proceduresset-forth by the Clinical and Laboratory Standards Institute (CLSI) andUS Pharmacopeia.

-   -   i. E. coli was chosen as the bacteria to challenge the stability        of the bound compositions and the free hydrogen peroxide.    -   ii. The hydrogen peroxide concentration was matched to the        selected bacteria in order to form a useful curve representing        hydrogen peroxide degradation over time for the samples. As        such, the hydrogen peroxide was varied from 62.5 ppm to 500 ppm        on a fixed E. coli concentration of 10⁶ CFU/ml, and a        concentration of 125 ppm was chosen as the initial hydrogen        peroxide level used to challenge the E. coli over time.    -   iii. A ratio of 1:1 of the hydrogen peroxide to each of the        model compounds and plant extracts was used to form each bound        composition, such that 125 ppm of each plant extract was        combined with the 125 ppm of the hydrogen peroxide.    -   iv. The free hydrogen peroxide was added at a concentration of        125 ppm as a control to show the relative stability of the        hydrogen peroxide alone in the aqueous solution as compared to        the bound compositions.

FIGS. 2A and 2B show that the stability of the hydrogen peroxide in thecombination is consistently, substantially greater in an aqueoussolution than the stability of the hydrogen peroxide alone in theaqueous solution, according to some embodiments. FIG. 2A comparesstabilities of free hydrogen peroxide to hydrogen peroxide bound to eachof: gallic acid (a model polyphenol building block), tannic acid (amodel polyphenol), pomegranate husk extract, green tea extract, andBlessed thistle extract. FIG. 2B shows very similar and consistentstabilities when comparing free hydrogen peroxide to hydrogen peroxidebound to a wide variety of species of plants: Aloe, Angelica, BarberryRoot Bark, Bilberry, Calendula, Cramp bark, Eleutherococcus root, Kidneywood, Mimosa tenuiflora, Papaya leaves, Pau D'Arco, Sassafras albidumroot bark, Saw Palmatto, St. John's wort, Valerian, Apple, Grape,Echinacea purpurea, Grape seed extract, and Blueberry. In both

FIGS. 2A and 2B, there are curves that cannot be identified wellindividually, as they are identical and overlapping. The free hydrogenperoxide curve does not overlap with any of the bound compositionsbeyond the 4 hour mark. Table 1 provides data used to produce the curvesin the overlap for clarity.

TABLE 1 Hours 0 4 8 12 16 20 24 Aloe (Aloe vera) 125 30 25 20 15 15 10Angelica (Angelica archangelica) 125 16 15 12 10 10 12 Barberry(Berberis vulgaris) Root Bark 125 30 20 15 10 10 12 Bilberry (Vacciniummyrtillus) 125 30 25 20 15 12 15 Calendula (Calendula officinalis) 12516 15 12 10 10 10 Cramp bark (Viburnum opulus) 125 16 12 10 10 12 12Eleutherococcus root 125 16 12 10 10 10 10 (Eleutherococcus senticosus)Kidney wood 125 16 12 10 10 10 10 (Eysenhardtia orththocarpa) Mimosatenuiflora 125 30 25 15 10 12 15 Papaya (Carica papaya) leaves 125 16 1210 10 12 15 Pau D' Arco (Tabebuia avellanedae) 125 20 15 10 10 12 10Sassafras albidum root bark 125 20 15 10 10 10 12 Saw Palmatto (Serenoarepens) 125 15 12 10 10 10 12 St John's wort (Hypericum perforatum) 12540 25 20 12 15 12 Valerian (Valeriana officinalis) 125 20 15 12 10 10 12Apple (Malus domestica) 125 15 11 10 10 10 10 Grape (Vitis vinifera) 12530 20 15 15 12 12 Echinacea purpurea 125 16 15 12 12 10 10 Grape seedextract 125 30 20 15 10 10 10 Blueberry (Vaccinium corymbosum) 125 20 1512 10 10 10 H2O2 125 15 0 0 0 0 0

The results were quite impressive and surprising, as the free hydrogenperoxide degraded quickly to near 0.0 ppm each time within about thefirst 8 hours, whereas each of the bound compositions maintained atleast 10 ppm or greater for the total duration of the study, which waslimited due to time constraints. As such, it was observed that thestabilities were maintained at a concentration of at least 10 ppm orgreater for at least 24 hours, a concentration sufficient to maintainbactericidal activity in water. FIG. 2A shows that at least 7 days ofstability remained present in at least the samples that were affordedthe at least 7 days of testing. In fact, potencies have been observed toremain in the compositions when challenged for at least 30 days, and theoriginal batches have shown to remain potent for at least 90 days, insome cases.

Example 2 Treating Gastrointestinal Spasms in Patients Having IrritableBowel Syndrome

A physician-controlled, open-label pilot study of 29 patients wasperformed. The patients suffered chronic gastrointestinal symptoms,including gastrointestinal spasms, and were selected because they wereeither non-responsive, or merely partially responsive, to standardtreatments. The patients had been diagnosed with irritable bowelsyndrome (IBS) and ranged in age from 29 years old to 79 years old,having a mean age of 51 years old. 83% of the patients were female. Thepatients were provided with sufficient volume of the composition forfive days of consumption and asked to note any response or effects ofthe extract. Each of the patients received a 25 ml bottle of the testcomposition and instructed to take 5 ml per day with water at least 1hour before meals for a 5 day period. The patients had been undertreatment for chronic GI distress for an extended period and were askedto compare the performance of the test composition against their ownsubjective baseline health.

The Test Composition

The test solution (“the composition” or “the test composition”)contained approximately 1100 micrograms total dry weight of dessicatedpomegranate and green tea extract dissolved in a solution of 0.05%hydrogen peroxide in purified water. 25 ml was of the solution was thenfurther diluted in 250 ml of oral rehydration solution to a finalconcentration of 0.0045% hydrogen peroxide and 100 micrograms ofpolyphenols before administration. Unused and undiliuted solutions ofthe composition from the same lot were tested for hydrogen peroxideconcentration using standard methodologies, described herein, verifyingan unchanged ratio of peroxide to polyphenols. The free hydrogenperoxide at the fully diluted oral concentration was well below itsconventionally accepted minimum inhibitory concentration for mostbacteria.

The composition was tested for stability. Consistent with the methodstaught herein, the composition was dessicated to a gummy solid with slowheating in a glass dish or beaker at 45-65° C. under constant, gentlemixing, along with vacuum dessication to degrade free hydrogen peroxide.The composition was then rehydrated to its original liquid volume todetermine the amount of hydrogen peroxide that was stable enough toremain in the composition. And, to compare the composition to thoseprepared from other plant tissues, the same test was performed with avariety of polyphenol extracts including grape skin extract, guava leafextract, green tea extract only, pomegranate rind only, Aloe vera skinextract, and knotweed extract. All of the compositions retained asubstantial concentration of a stable, hydrogen peroxide through thedessication and rehydration cycle, providing evidence that waterextracts from different plant sources provide a source of polyphenolsthat form similar stable compositions with hydrogen peroxide.

The Study

Significant responses to administration of the composition wereobserved. Of the 29 patients, 4 complained of constipation and 2 showedimprovement. The 6 out of the 13 with gluten sensitivity (a test used inthe diagnosis of IBS) reported reduced incidence of bloating, abdominalpain, bowel urgency or soft/water stools following gluten intake,suggesting that the composition is an effective treatment for irritablebowel syndrome. 19 out of the 29 (65%) subjects generally reported animproved health and relief of symptoms. 11 out of 16 (69%) of thesubjects, a rather high percentage, reported improvement ingastrointestinal spasm symptoms. It has been observed, generally, thatsubjects receiving the composition have reported significantimprovements over their historic baseline health within 24 hours.

A Literature Comparison

As described above, loperamide can be used to treat symptoms of IBS. Asan agent for IBS patients, loperamide has been reported to resolveabdominal pain symptoms in 56% to 59% of patients in one study but to beno different from placebo in other studies. See, for example, Kaplan MA, et al. Arch Fam Med 8: 243-248 (1999); Efskind, P S, et al. Scand JGastroenterol 31: 463-468 (1996); Cann P A, et al. Dig Dis Sci 29(3):239-247 (1984); and, Jailwala J, TF Imperiale, K Kroenke. Ann Intern Med133: 136-147 (2000). Antispasmotic medications have been reported toresult in a higher level of relief of abdominal pain than placebo, withup to 56% of patients experiencing a result that was clinicallymeaningful. See, for example, Trinkley K E, et al. J Clin Pharm Thera36: 275-282(2011); and, Page J G, et al. J Clin Gastroenterol 3: 153-156(1981).

In comparison, the results to date suggest that the compositions taughtherein offer a significant improvement over the results that have beenobserved in the literature for loperamide, for example, at least withregard to the treatment of IBS.

Other Studies

Other compositions using polyphenols derived from water extractions fromother plants have been tested and shown to provide similar results. Inone study, grape skin extract and guava leaf extract have been combinedwith commercial food grade hydrogen peroxide and plant extractedhydrogen peroxide from aloe vera gel. This composition was administeredto human subjects suffering from abdominal cramps. In all cases, theadministration provided effective relief, evidence that other sources ofwater soluble polyphenol extracts provide commercially valuable andeffective antispasmodic compositions.

In another study, 46 adults (including 6 having IBS) experiencingvomiting, abdominal pain, cramps, and bloating were given the 25 mlsolution of the combination of composition (green tea/pomegranate/H2O2)and reported near-immediate relief with a significant reduction insymptoms remaining after 24 hours of treatment when compared to aplacebo group. 78% reported significant benefit.

Example 3 Prophylactic Inhibition or Prevention of AlcoholOverindulgence

Experimental prophylactic use of the compositions has shown in a varietyof subjects that it can inhibit or prevent gastrointestinal symptoms ofthe over consumption of alcohol. Surprisingly, it was also effective atinhibiting or preventing other symptoms of excess alcohol consumption.For example, the symptoms that have been prevented or inhibited havebeen measured against the historic baseline of the subject, including analcohol-induced headache; and, alcohol-induced dermal and other tissuereactions such as apparent immune-type, allergenic reactions thatincluded itchiness, blotchiness, flushing, red eyes, and runny nose.

Prior to the consumption of alcohol at a social event, each of thesubjects consumed approximately 2000 ug-5000 ug of a greentea/pomegranate composition (dry weight) with water. The greentea/pomegranate that was administered was from a variety of lots andvaried in ratio from 1:1 to 4:1 wt/wt. The subjects consumedapproximately 2-10 alcoholic drinks, mixed and/or straight, ranging incontent from about 5% to about 60% alcohol. The drinks ranged in contentfrom wine to beer to liqueurs to liquors, and combinations thereof. Eachof the subjects expressed that the composition provided a substantialprophylactic effect to inhibit or prevent the effects of the alcoholconsumption, using their own, personal historic baselines of what theyexpected to experience without consuming the composition prior todrinking.

The experiments shown herein are for illustration and example only. Oneof skill can vary the experimental conditions and components to suit aparticular or alternate experimental design. The experimental conditionscan be in vitro or in vivo, or designed for any subject, for example,human or non-human. For example, animal testing can be varied to suit adesired experimental method. As such, one of skill will appreciate thatthe concepts can extend well-beyond the examples shown, a literalreading of the claims, the inventions recited by the claims, and theterms recited in the claims.

We claim:
 1. A method of treating a gastrointestinal spasm in a subjecthaving Crohn's disease or ulcerative colitis, the method comprising:administering an effective amount of a composition to a subject having agastrointestinal spasm, the composition having a water solublepolyphenol that was (i) water-extracted from a mixture of pomegranatehusk and green tea leaf and (ii) combined with hydrogen peroxide priorto the administering; wherein, the hydrogen peroxide concentrationranges from about 0.001% to about 1% based on total dry weight of thecomposition; the polyphenol comprises a tannin; the polyphenol has amolecular weight ranging from about 170 Daltons to about 4000 Daltons;and, the composition relieves a gastrointestinal spasm in the subjecthaving Crohn's disease or ulcerative colitis when compared to secondsubject in a control group also having Crohn's disease or ulcerativecolitis in which the composition was not administered.
 2. The method ofclaim 1, wherein the relief of the spasm is measured using a responseselected from the group consisting of a reduction in abdominal pain, areduction in bloating, a reduction in forceful defecation, a reductionin forceful vomiting, a reduction in defecation urgency, a reduction inconstipation, and a reduction in incontinence.
 3. The method of claim 1,wherein the polyphenol comprises a hydrolysable tannin.
 4. The method ofclaim 1, wherein the polyphenol comprises a water soluble condensedtannin.
 5. The method of claim 1, wherein the polyphenol comprises acombination of a hydrolysable tannin and a water soluble condensedtannin.
 6. The method of claim 1, wherein the polyphenol comprises aflavanol.
 7. The method of claim 1, wherein the polyphenol comprises acatechin.
 8. The method of claim 1, wherein the polyphenol comprisesgallic acid, epigallic acid, or a combination thereof.
 9. The method ofclaim 1, wherein the composition is administered in combination with anoral rehydration solution.
 10. The method of claim 1, wherein thepolyphenol includes an ellagitannin and a gallotannin.
 11. The method ofclaim 1, wherein the polyphenol includes a punicalagin.
 12. A method oftreating a gastrointestinal spasm in a subject having Crohn's disease orulcerative colitis, comprising: administering an effective amount of acomposition to a subject having a gastrointestinal spasm, thecomposition produced from a process including extracting a water solublepolyphenol from a combination of green tea leaf and pomegranate husk;combining the polyphenol with hydrogen peroxide prior to theadministering; wherein, the polyphenol has a molecular weight rangingfrom about 170 Daltons to about 4000 Daltons; selecting a desiredconcentration for the composition; and, diluting the composition to thedesired concentration for the administering; wherein, the hydrogenperoxide concentration ranges from about 0.001% to about 1% based ontotal dry weight of the composition; the polyphenol comprises a tannin;and, the composition relieves a gastrointestinal spasm in the subjecthaving Crohn's disease or ulcerative colitis when compared to a secondsubject in a control group also having Crohn's disease or ulcerativecolitis in which the composition was not administered.
 13. The method ofclaim 12, wherein the relief of the spasm is measured using a responseselected from the group consisting of a reduction in abdominal pain, areduction in bloating, a reduction in forceful defecation, a reductionin forceful vomiting, a reduction in defecation urgency, a reduction inconstipation, and a reduction in incontinence.
 14. The method of claim12, wherein the polyphenol comprises a hydrolysable tannin.
 15. Themethod of claim 12, wherein the polyphenol comprises a water solublecondensed tannin.
 16. The method of claim 12, wherein the polyphenolcomprises a combination of a hydrolysable tannin and a water solublecondensed tannin.
 17. The method of claim 12, wherein the polyphenolcomprises a flavanol.
 18. The method of claim 12, wherein the polyphenolcomprises a catechin.
 19. The method of claim 12, wherein the polyphenolcomprises gallic acid, epigallic acid, or a combination thereof.
 20. Themethod of claim 12, wherein the polyphenol includes an ellagitannin anda gallotannin.
 21. The method of claim 12, wherein the polyphenolincludes a punicalagin.
 22. A method of treating a gastrointestinalspasm in a subject suffering from Crohn's disease or ulcerative colitis,comprising: administering an effective amount of a composition to asubject having a gastrointestinal spasm, the composition produced from aprocess including obtaining a water extract from a green tea leaf and awater extract from a pomegranate husk; combining the water extract fromthe green tea leaf and the water extract from the pomegranate husk toform a mixture of polyphenols having a molecular weight ranging fromabout 170 Daltons to about 4000 Daltons; and, adding hydrogen peroxideto the polyphenol prior to the administering, the hydrogen peroxideconcentration selected from a group consisting of concentration rangesfrom about 0.001% to about 1.5%, from about 0.001% to about 1%, fromabout 0.001% to about 0.1%, each range based on total dry weight of thecomposition; wherein, the polyphenol comprises a tannin; and, thecomposition relieves a gastrointestinal spasm in the subject sufferingfrom Crohn's disease or ulcerative colitis when compared to the baselinehealth of the subject prior to the administering.